IL99913A - 2-Saccharinylmethyl aryl carboxylates their preparation and pharmaceutical compositions containing them - Google Patents

Description

o nn xnpmi >-I >YOJII tuuDfi ,ο>ν>;?>ορϊ:ηρ !?>->M ^ nni> J > ~IDO-2 2-Saccharinylmethyl aryl carboxylates, their preparation and pharmaceutical compositions containing them STERLING WINTHROP INC.

C: 84709 NOVEL 2-SACCHARINYLMETHYL ARYL CARBOXYLATES USEFUL AS PROTEOLYTIC ENZYME INHIBITORS AND COMPOSITIONS AND METHOD OF USE THEREOF BACKGROUND OF THE INVENTION (a) Field of the Invention This invention relates to novel 2-saccharinyl-methylaryl carboxylates, which inhibit the enzymatic activity of proteolytic enzymes, to compositions containing the same, to the method of use thereof in the treatment of degenerative diseases and to processes for thei preparation . (b) Information Disclosure Statement The inhibition of proteolytic enzymes by nontoxic reagents is useful in the treatment of degenerative disor-ders, such as emphysema, rheumatoid arthritis and pancreatitis, in which proteolysis is a substantive element.

Protease inhibitors are widely utilized in biomedical research. Serine proteases are the most widely distributed class of proteolytic enzymes. Some serine proteases are characterized as chymotrypsin-like or elas-tase-like based upon their substrate specificity.

Chymotrypsin and chymotrypsin-like enzymes normally cleave peptide bonds in proteins at a site at which the amino acid residue on the carboxyl side is typically Trp, Tyr, Phe, Met, Leu or another amino acid residue which contains aromatic or large alkyl side chains.

Elastase and elastase-like enzymes normally cleave peptide bonds at a site at which the amino acid residue on the carboxyl side of the bond is typically Ala, Val, Ser, Leu or other similar, smaller amino acids.

Both chymotrypsin-like and elastase-like enzymes are found in leukocytes, mast cells and pancreatic juice in pancreatic juice in higher organisms, and are secreted by many types of bacteria, yeast and parasites.

Japanese Patent Publication 7200419 discloses a number of 2-saccharinyl- methylbenzoates, including 2-saccharinylmethyl benzoate per se and 2-saccharinylmethyl 2, 4-dichlorobenzoate and 4-nitrobenzoate . The compounds are said to "have strong activity against rice blast, rice sheath blight, rice helminthosporium leaf spot and rice bacterial leaf t o blight disease".

Sunkel et al., J. Med. Chem., 3J_, 1886-1890 (1988) disclose a series of 2-saccharinyl-lower-alkyl- 1, 4-dihydro-pyridine-3-carboxylates having platelet aggregation inhibitory and anti-thrombotic activities. 15 Chen U.S. Patent 4,263,393 discloses various 2-aroylmethylsaccharins useful as "photographic elements and film units".

Mulvey et al. U.S. Patent 4,195,023 discloses R1-2-R2CO-I, 2-benzisothiazol- 0 3-ones, where R^ is halogen, alkoxy, alkylamino, dialkylamino, alkoxycarbonyl, amino, nitro or hydrogen in the benzenoid ring and R2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halophenyl, heteroaryl or substituted heteroaryl, and Ri-2-A-CO saccharins, where 5 Ri has the same meanings as the benzenoid ring substituents in the 1, 2-benzisothiazol-3-ones and A is alkyl, alkenyl, alkynyl, cycloalkyl, fluorophenyl, heteroaryl or substituted-heteroaryl . The compounds are said to have elastase inhibitory activity and to be 30 useful in the treatment of emphysema.

Zimmerman et al., J. Biol. Chem., 22-5.(20), 9848-9851 (1980) disclose N-acylsacchar ins , where the acyl group is furoyl, thenoyl, benzoyl, cyclopropanoyl, ethylbutyryl and acryloyl, having serine protease inhibitory activity.

Japanese Patent Publication 73/35457 discloses 4-methylphenyl 2-saccharinyl-carboxylate which is said to have bactericidal and fungicidal activities.

Several classes of compounds are known to be serine protease inhibitors. For example Powers U.S. Patent 4,659,855 discloses arylsulfonyl fluoride derivatives useful as elastase inhibitors. Doherty et al. U.S. Patents 4,547,371 and 4,623,645 disclose cephalosporin sulfones and sulfoxides, respectively, which are stated to be potent elastase inhibitors useful in the treatment of inflammatory conditions, especially arthritis and emphysema.

Teshima et al., J. Biol. Chem., 21.2(9), 5085- 5091 (1982) report the results of studies on serine proteases (human leukocyte elastase, porcine pancreatic elastase, cathepsin G and bovine chymotrypsin Aa) with 4-nitrophenylesters and thioesters of N-trifluoroacetylanthranilates, 2-substituted-4H-3, 1-benzoxazin-4-ones, 2-substituted-4-quinazolinones and 2-substituted-4-chloroquinazolines .

Cha, Biochem. Pharmacol., 21, 2177-2185 (1975) discusses kinetic approaches to the study of the binding of inhibitors to macromolecules, such as enzymes, and methods for determination of such parameters as the inhibition constants, reaction rates and bound and unbound enzyme concentrations.

Jones et al., U.S. Patent 4,276,298 discloses 2-R-l, 2-benzisothiazolinone-l, 1-dioxides, where R is phenyl substituted by fluoro, dinitro, trif luoromethyl, cyano, alkoxycarbonyl, alkylcarbonyl, carboxyl, carbamoyl, alkylacylamino, al kylsulfonyl , N,N- dialkylsulfamoyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl and trifluoromethylsulfinyl, or pyridyl substituted the same as R when R is phenyl except that pyridyl may also be mononitro substituted. The compounds are said to have protease enzyme inhibitory activity, especially elastase inhibitory activity, and to be useful in the treatment of emphysema, rheumatoid arthritis "and other inflammatory diseases".

Powers, Biochem., 21, 2048-2058 (1985) discloses studies of the inhibitions of four chymotrypsin-like enzymes, cathepsin G, rat mast cell proteases I and II, human skin chymase and chymotrypsin Αβ, by N-furoylsaccharin and N-(2,4-dicyanophenyl) saccharin .

Svoboda et al., Coll. Czech. Chem. Commun,, 51, 1133-1139 (1986) disclose the preparation of 4-hydroxy-2H-l, 2-benzothiazine-3-carboxylates by intramolecular Dieckmann condensation of 2H-1,2-benzisothiazol-3-one-2-acetate-l, 1-dioxide esters.

Reczek et al. U.S. Patents 4,350,752 and 4,363,865 and Vanmeter et al. U.S. Patent 4,410,618 relate to photographic reagents (Reczek 4,350,752 and Vanmeter et al . ) and photographic dyes (Reczek 4,363,865) and disclose various 2-^substituted-saccharins useful for such applications, for example "photographic reagents" bound through a heteroatom to an "imidomethyl blocking" group (Reczek 4,350,752), "carrier-diffusible photographic dyes" bound to the nitrogen atom of an imide through a 1,1-alkylene group (Reczek 4,363,865) and N-acylmethylimides which are described as "blocked photographic reagents" and which have a "residue of an organic photographic reagent containing a hetero atom through which it is bound to the blocking group" (Vanmeter) .

Freed U.S. Patent 3,314,960 discloses 2- (1,1, 3-trioxo-l, 2-benzisothiazol-2-yl) glutarimides which are stated to be useful as sedatives. 2-Chloromethylsaccharin is disclosed in French Patent 1,451,417 as an intermediate for the preparation of N-methylsaccharin d, 1-trans-chrysanthemate, useful as an insecticide, and Lo U.S. Patent 3,002,884 discloses 2-chloro, 2-bromo and , useful as fungicidal agents.

SUMMA Y OF THE INVENTION In a composition of matter aspect, this invention relates to 4-R4-R^-2-saccharinylmethyl aryl carboxylates and 4, 5, 6, 7-tetrahydro-2-saccharinylmethyl aryl carboxylates which have protease enzyme inhibitory activity and which are useful in the treatment of degenerative diseases.

In a composition aspect, the invention relates to compositions for the treatment of degenerative diseases which comprise a pharmaceutical carrier and an effective proteolytic enzyme inhibiting amount of a 4-R^-R^-2-saccha-rinylmethyl aryl carboxylate or a 4 , 5, 6, 7-tetrahydro-2-saccharinylmethyl aryl carboxylate.

In a method aspect, the invention relates to a method of use of said 2-saccharinylmethyl aryl carboxylates in the treatment of degenerative diseases which comprises administering to a patient in need of such treatment a medicament containing an effective proteolytic enzyme inhibiting amount of a 4-R/'-R5-2-saccharinylmethyl aryl carboxylate or 4 , 5, 6, -tetrahydro-2-saccharinylmethyl aryl carboxylate.

In process aspects, the invention relates to processes for the preparation of said 4-R^-R5-2-saccharinyl-methyl aryl carboxylates and , 5, 6, 7-tetrahydro-2-saccharinylmethyl aryl carboxylates which comprise reacting (1) a 2-halomethylsaccharin with an aryl carboxylic acid in the presence of an acid-acceptor, or (2) reacting a saccharin with a chloromethyl ester of an aryl carboxylic acid in the presence of an acid acceptor, or (3) reacting an alkali metal or thallium salt of the appropriate acid with the appropriate halomethyl species.

SUMMA Y OF Til F TMVEMTTOM In a composition of matter aspect, this invention relates to l-R^-RS^-saccharinylmethyl aryL carboxylates * which have protease enzyme inhibitory activity and w ich are useful in the treatment of degenerative diseases .

In a composition aspect, the invention relates to compositions for the treatment of degenerative diseases which comprise a pharmaceutical carrier and an effective proteolytic enryme inhibiting amount of a A-R'^-R^-Z-saccha- rinyirnethyi aryl carboxylate. . .

In process aspects, the invention relates to processes for the preparation of said 4-R1-Sl5-2-saccharinyl- methyi aryl carboxylates which comprise reacting (1) a 2-haicmel:hyisaccharin with an aryl car'ooxylic acid in the presence of an acid-acceptor, or (2) reacting a saccharin with a chi.o ome yi ester of an aryl car'ooxylic acid, in the presence of an acid acceptor, or (3) reacting an alkali metal or thallium salt of the appropriate acid with the appropriate halomethyl species.

DETAILED DESCRIPTION OE T!E ?P.E".?.REO EMBODIMENTS More specifically this invention relates to 4-R4- p5_2-saccharinylmethyl aryl carboxylates having the formula: wherein: ■ · Ar is phenyl, nap thyi or anthryi or such roups substituted by from one to three, the same- or different, members of the grou consisting of iover-aikyi, pe rfiuor iowe -ai!-c i, perchiorclower-aikyi, iower- lkcxy , 31.X.91 halogen, nitro, cyano, carboxy, 0 ?0 ( io er-ai!2f where R is lower-alkyl; R4 is hydrogen, primary or secondary-lower-alkyl, lower-alkoxy or phenyl; and R5 is hydrogen, hydroxy, lower-alkoxy, methylenedioxy, cycloalkyloxy, hydroxylower-alkoxy, polyhydroxylower-alkoxy, or acetal or ketal thereof, poly (lower-alkoxy) lower-alkoxy, -0- (alkylene) -COOR, or 0- (alkylene) -N=B or R5 is a [6,5-g]fused 1,3-oxazine Particularly preferred compounds of formula I are those wherein: Ar is phenyl or phenyl substituted by from one to three, the same or different, members selected from the group consisting of lower-alkyl, lower-alkoxy, halogen, hydroxy, carboxylower-alkoxy, benzyloxy, -S02- =B or -0- (alkylene) -N*=B, where N=B is dilower-alkylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinyl, 4-lower-alkyl-l-piperazinyl, 4-benzyl-l-piperazinyl, carboxylower-alkylamino or -NR- (alkylene) -N (alkyl) 2/ where R is lower-alkyl; R4 is primary or secondary lower-alkyl or lower-alkoxy; and R5 is hydro-gen, lowex-alkoxy, methylenedioxy, cycloalkyloxy, hydroxylower-alkoxy, polyhydroxylower-alkoxy, or acetal or ketal thereof, poly (lower-alkoxy) lower-alkoxy, -0- (alkylene) -COOR, or -0- (alkylene) -N=B . '. ~~~ Other preferred compounds of formula I are those wherein: Ar is phenyl, naphthyl or anthryl, or phenyl substituted by from one to three, the same or different, members selected from the group consisting of lower-alkyl, perfluoro-lower-alkyl, lower-alkoxy, halogen or lower-alkanoylamino; R< is hydrogen, primary or secondary lower- alkyl, lower-alkoxy or phenyl; and R5 is hydrogen or lower-alkoxy.

Still other preferred compounds of formula I are these wherein: Ar is phenyl or phenyl substituted by from one to three, the same or different, members selected from the group consisting of lower-alkoxy, halogen or lower- alky1; is hydrogen, primary or secondary-lower- alkyl or lower-alkoxy; and R5 is hydroxy in any of the 5-, 6- or 7- positions.

The compounds having the general structural formula I are usually named in the chemical literature as 1, 2-benzisothiazol-3 (2H) -one 1, 1-dioxides . However for the sake of brevity, such compounds are frequently named as saccharin derivatives, and that nomenclature will be used hereinafter in describing the compounds of the invention and their biological properties.

As used herein the terrr.s lower-aikyl, lower-alkcxy and lower-aikane mean mcr. : = ie.nc aliphatic radicals, including branched chain radicals, of from one to ten carbon atoms . Thus the lower-alkyl (or lower-alkane) moiety of such groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, 2-methyl-3-butyl, 1-methylbutyl, 2-methylbutyl, neopentyl, n-hexyl, 1-methylpentyl, 3-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 2-hexyl, 3-hexyl, 1, 1, 3, 3-tetramethylpentyl, 1, 1-dimethyloctyl and the like.

As used herein the term halogen (or halo) means fluorine, chlorine, bromine or iodine.

As used herein the terms lower-alkenyl and lower-alkynyl mean monovalent, unsaturated radicals, including branched chain radicals, of from two to ten carbon atoms and thus include 1-ethenyl, 1- (2-propenyl) , 1- (2-butenyl) , 1- (l-methyl-2-propenyl) , 1- (4-methyl-2-pentenyl) , 4, , 6-trimethyl-2-heptenyl, 1-ethynyl, l-(2-propynyl) , 1- (2-butynyl) , 1- (l-methyl-2-propynyl) , 1- (4-methyl-2-pentynyl) , and the like.

As used herein, the term alkylene means divalent, saturated radicals, including branched chain radicals, of from two to ten carbon atoms and having their free valences on different carbon atoms and thus includes 1, 2-ethylene, 1, 3-propylene, 1, -butylene, 1-methyl-1, 2-ethylene, 1,8-octylene and the like.

As used herein cycloalkyl means C3 through C7 saturated monocyclic hydrocarbon residues and thus includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The compounds of the present invention inhibit the activity of serine proteases, specifically human leukocyte elastase and the chymotrypsin-like enzymes, and are thus useful in the treatment of degenerative disease conditions such as emphysema, rheumatoid arthritis, pancreatitis, cystic fibrosis, chronic bronchitis, adult respiratory distress syndrome, inflammatory bowel disease, psoriasis, bullous pemphigoid and alpha-l-antitrypsin deficiency.

The compounds of formula I are prepared by reaction of a 2-halomethylsaccharin with an appropriate aryl carboxylic acid, Ar-COOH or by reaction of a saccharin or tetrahydrosaccharin with a chloromethyl ester of an aryl carboxylic acid. 0 ClCH2OC IIAr II The reaction can either be carried out in the presence of a acid-acceptor, such as an alkali metal carbonate, a trilower-alkylamine or 1, 8-diazabicyclo- [5.4.0] undec-7-ene, hereinafter DBU. Alternatively the salt of an alkali metal, especially cesium or thallous salt of the aryl carboxylic acid can be used (prepared by reaction of the acid with an alkali metal carbonate or thallous lower-alkoxide) . The reaction is carried out in an organic solvent inert under the conditions of the reaction, for example acetone, methyl ethyl ketone ( EK) , acetonitrile, tetrahydrof ran (TKF) , diethyl ether, dimethylformamide (DMF) , N-methylpyrrolidinone, methylene dichloride (MDC) , xylene, toluene or lower-alkanols, at a temperature in the range from ambient up to the boiling point of the solvent used.

The 4- 4-R^-2-halomethylsaccharins required for the preparation of the compounds of formula I are prepared by the methods described by D'Alelio et al., J. Macromol. Sci-Chem., £2(5), 941 (1969) and Saari et al., J. Het. Chem., 22/ 1253 (1986).

In the method described by Saari, a methyl ester of an appropriate anthranilic acid is prepared by conventional means from the substituted anthranilic acid and the ester diazotized. The diazonium salt is then reacted with sulfur dioxide and cupric chloride to produce a sulfonyl chloride which is then reacted with concentrated ammonium hydroxide to produce the substituted saccharin derivatives of formula II. The latter, on reaction with formaldehyde in a lower-alkanol solvent, affords the 4-R4-R5-2-hydroxymethylsaccharins of formula III, which, on reaction with a thionyl halide or a phosphorus trihalide, afford the corresponding 4-R^-R5-2-halomethylsaccharin derivatives of formula IV.

The 4-R4-R^-2-halomethylsaccharins of formula IV, where X is chlorine or bromine, can also be prepared by reaction of a corresponding 4-R4-R5-2-phenyl-thiomethylsaccharin with a sulfuryl halide in an inert organic solvent, for example DC, ethylene dichloride (EDO or carbon tetrachloride, at a temperature from around 0°C to around 30°C. The 4-R4-R5-2-phenylthiomethylsaccharins are in turn prepared by reaction of a 4-R4-R5-saccharin of formula II with a halomethylphenyl sulfide in an inert organic solvent, such as toluene, xylene, D F or MDC at a temperature in the range from ambient up to the boiling point of the solvent used. The reaction can be carried out by reaction of the halomethyl phenyl sulfide with either the thallium salt of the saccharin derivative of formula II (prepared by reaction of the saccharin derivative with a thallium lower-alkoxide in a lower-alkanol) ; or with a di-lower-alkyl ammonium salt of the saccharin derivatives (prepared as described below) in the presence of a tetra-lower-alkyl ammonium halide, such as tetrabutyl ammonium bromide (hereinafter TBAB) ; or with the saccharin derivative of formula II per se in the - - presence of a tetralower-alkyl ammonium halide; or with the saccharin derivative of formula II per se in the presence of a tetralower-alkyl ammonium halide and an alkali metal lower-alkoxide, such as potassium t-butoxide .

The saccharins of formula II may also be converted to the chloromethyl saccharins of formula IV, wherein X is CI, in one step by reaction with an excess of formaldehyde or a formaldehyde equivalent, such as paraformaldehyde or 1, 3, 5-trioxane, and a chlorosilane, preferably chlorotrimethylsilane in the presence of a Lewis acid, preferably a catalytic amount of stannic chloride in an inert solvent, preferably 1,2-dichloroethane (ethylene dichloride, EDC) .

All of the conversions of the saccharins II to the 2-chloromethyl saccharins IV are equally applicable to the conversion of tetrahydrosaccharins VII to 2-chloromethyl tetrahydrosaccharins VIII.

The compounds of formula II can also be prepared by reaction of a 2-R^- ^-N,N-di-lower-alkylbenzamide of formula V with one molar equivalent of a lower alkyl alkali metal, such as lithium, optionally in the presence of a tetralower-alkylethylenediamine, in an inert organic solvent, for example THF, and reaction of the resulting alkali metal salt either with sulfur dioxide at a temperature in the range from -50° to -80eC followed by reaction of the resulting alkali metal sulfinate with hydroxylamine-O- sulfonic acid in the presence of base, or with a sulfuryl halide followed by ammonia. When the sulfur dioxide-hydroxylamine-O-sulfonic acid route is used, it is particularly advantageous to neutralize the hydroxylamine-O-sulfonic acid with one equivalent of sodium hydroxide prior to addition of the alkali metal sulfinate. The resulting 2-R4-R5-6-aminosulfohyl- , N- dilower-alkylbenzamide is thereafter heated in an acid medium to effect cyclization of the lacter to produce the dilower-alkyl ammonium salt of the desired 4-R4-R5-saccharin of formula II, which can be used as such in the subsequent reaction or, if desired, can be hydrolyzed in dilute acid and the free saccharin isolated. It is preferred to carry out the cyclization in refluxing glacial acetic acid. The method is illustrated as follows where R4, R^ and Alk have the meanings given above, and the alkali metal is lithium.

The compounds of formula II where R4 is either primary or secondary lower-alkyl, and which are useful as intermediates for the preparation of the compounds of formula I as described above, are prepared by one of two methods . The compounds of formula II where R4 is primary lower-alkyl are prepared by reacting a 4-methyl-R^-saccharin (formula II, R4 is CH3) with two molar equivalents of a lower-alkyl alkali metal, such as lithum in an inert organic solvent, for example THF, and reacting the resulting alkali metal salt with one molar equivalent of a lower-alkyl halide^-both reactions being carried out at a temperature in the range from about -50°C to -80°C .

Another method for preparing the compounds of formula II where R4 is either primary or secondary lower-alkyl comprises reaction of a 2-primary-lower-alkyl-R5-N, -di-lower-alkylbenzamide (formula V, R4 is primary-lower-alkyl ) with one molar equivalent of a lower-alkyl alkali metal or an alkali metal dilower-alkylamide, wherein the alkali metal is especially lithium optionally in the presence of a tetralower-alkylethylenediamine, in an inert organic solvent, for exmple THF, and reaction of the resulting alkali metal salt with one molar equivalent of a lower-alkyl halide at a temperature in the range from about -50°C to -80°C . The resulting 2-primary or secondary-lower-alkyl-R^-N, N-di- lower-alkyl-benzamide is thereafter converted to the compounds of formula I I, where R4 is primary or secondary lower-alkyl, by the same sequence of reactions described above, i . e . by reaction of the 2-primary or secondary-lqwer-alkyl-R5-N, N-di-lower-alkylbenzamide with one molar equivalent of a lower-alkyl alkali metal, such as lithium; reaction of the resulting alkali metal salt either with sulfur dioxide followed by hydroxylamine-O-sulf onic acid in the presence of base or with a sulfuryl halide followed by ammonia; and cyclization of the product to the desired 4-primary or secondary-lower-alkyl- saccharin of formula I I . When the 2-lower-alkyl group in the 2-lower-alkyl-R^-N, N-di-lower-alkyl-benzamide starting material is methyl, alkylation affords species where the 2-lower-alkyl group is either straight or branched depending upon whether a straight or branched chain lower-alkylhalide is used for the alkylation . On the other hand, when the 2-lower-alkyl group in the starting material contains more than one carbon atom, alkylation takes place on the carbon atom adjacent the benzene ring and affords products having a sec . -lower- alkyl group at the 2-position .

A particularly useful method for the preparation of compounds II , where R4 is n-lower-alkyl and R5 is hydrogen involves the protection of the benzylic protons of the starting material V with a trialkylsilyl group, thereby permitting metalation, e.g. lithiation at the 6-position and formation of the sulfonamide as desribed above.

A 2-n-lower-alkylbenzamide wherein R8 is lower-alkyl is silylated by forming the benzylic anion using an alkyl alkali metal or, preferably, an alkali metal dilkylamide, wherein the alkali metal is especially lithium in an inert solvent, preferably THF, and treating 'with a suitable chlorotrialkylsilane, preferably chlorotrimethylsilane . The saccharin is synthesized as before, and the silyl group is removed by treatment with a source of fluoride anion, preferably cesium fluoride in DMF or tetra-n-butylammonium fluoride in an inert solvent .

Access to certain of the required intermediates in some cases requires building up the two rings making up "the saccharin or tetrahydrosaccharin nucleus . Thus to prepare saccharins where R4 is lower-alkoxy and R^ is 7-hydroxy, or tetrahydrosaccharins where R7 is lower-alkoxy, the following synthesis may be used : (SCH2CH2COOH)2 (SCH2CH2CONHBzl)2 BzNH2 (1) S02C12 (2) peracid 3, 3-Dithiobispropionic acid is converted to the bis acid chloride by reaction of the acid with thionyl chloride, and the acid chloride is then reacted with two molar equivalents of benzylamine to produce the bis N-benzylamide. The latter, on reaction with sulfuryl chloride in an organic solvent, such as MDC, EDC or carbon tetrachloride, affords 5-chloro-2-benzyl-2H-isothiazol-3-one, which is oxidized with one molar equivalent of a peracid, such as perbenzoic acid or 3-chloroperbenzoic acid, to 5-chloro-2-benzyl-2H-isothiazol-3-one-l-oxide . The latter, on heating under pressure with a 2-lower-alkoxyfuran in an organic solvent, such as benzene, toluene or xylene, affords a 4-lower-alkoxy-7-hydroxy-2-benzyl-l, 2-benzisothiazol-2H-3-one-l-oxide. The 7-hydroxy group can, if desired, then be reacted with a lower-alkyl halide or a lower-alkoxypoly-lower-alkoxy-lower-alkyl halide to give the corresponding 4, 7-di-lower-alkoxy or 4-lower-alkoxy-7-lower-alkoxypoly-lower-alkoxy-2-benzyl-l, 2-benzisothiazol-2H-3-one-l-oxide . Further oxidation of the product with one molar equivalent of a peracid as described above followed by catalytic debenzylation by transfer hydrogenation affords the corresponding 4-lower-alkoxy-7-hydroxysaccharins .

The aryl carboxylic acids, Ar-COOH, used to prepare the final products of formula I and VI are members of a known class and can be prepared by well- known, conventional synthetic methods.

Chloromethyl esters of the aryl carboxylic acid may be prepared by treating the carboxylic acid with formaldehyde or a formaldehyde equivalent, preferably paraformaldehyde, in the presence of (1) a chloro acid, preferably zinc chloride or hydrochloric acid, or (2) trimethylsilyl chloride plus stannic chloride.

Simple chemical transformations which are conventional and well known to those skilled in the art of chemistry can be used for effecting changes in functional groups in the compounds of the invention. For example, catalytic reduction of nitro groups to produce the corresponding amino substituted compounds, acylation of amino-substituted species to prepare the corresponding amides, oxidation of sulfides or sulfoxides to prepare the corresponding, respective sulfoxides or sulfones, saponification of esters to produce the corresponding carboxylic acids, catalytic debenzylation of phenolic ethers or of benzylamines to produce the corresponding phenols or debenzylated amines or reaction of phenols with an alkylating agent in the presence of base to produce ethers as desired can be carried out.

In standard biological test procedures, the compounds of formula I have been found to possess human leukocyte elastase (HLE) and chymotrypsin inhibitory activities, and are thus useful in the treatment of degenerative diseases, such as emphysema, rheumatoid arthritis, pancreatitis, cystic fibrosis, chronic bronchitis, adult respiratory distress syndrome, inflammatory bowel disease, psoriasis, bullous pemphigoid and alpha-l-antitrypsin deficiency.

The compounds of formula I having basic functions can be converted to the acid-addition salt form by interaction of the base with an acid. In like manner, the free base can be regenerated from the acid-addition salt form in conventional manner, that is by treating the salts with cold, weak aqueous bases, for example alkali metal carbonates and alkali metal bicarbonates . The bases thus regenerated can be interacted with the same or a different acid to give back the same or a different acid-addition salt. Thus the bases and all of their acid-addition salts are readily interconvertible.

Likewise certain compounds of formula I having acid, i.e. carboxylic acid, functions can be converted to salt forms thereof by reaction of the acid with a base, such as alkali metal or ammonium hydroxides or with organic bases such as alkyl, dialkyl or trialkylamines, and the acids can be regenerated from the salts by treatment of the salts with aqueous acids .

Formula. I not only represent the structural configuration of the bases and acids, but are also representative of the structural entities which are common to all of the comoounds of formula I - 28 - whether in the form of the free base, the free acids or in the form of the salts of the bases and acids. It has been found that, by virtue of these common structural entities, the compounds of formulas I and VI and their salts have inherent pharmacological activity of a type to be more fully described hereinbelow. This inherent pharmacological activity can be enjoyed in useful form for pharmaceutical purposes by employing the free bases or free acids themselves or the salts formed from pharmaceutically acceptable acids and bases; that is, acids or bases whose anions or cations are innocuous to the animal organism in effective doses of the salts so that beneficial properties inherent in the common structural entity represented by the free bases and free acids are not vitiated by side effects ascribable to the anions or cations.

In utilizing this pharmacological activity of the salt, it is preferred, of course, to use pharmaceutically acceptable salts. Although water insolubility, high toxicity or lack of crystalline character may make some particular salt species unsuitable or less desirable for use as such in a given pharmaceutical application, the water-insoluble or toxic salts can be converted to the corresponding pharmaceutically acceptable bases by decomposition of the salts with aqueous base or aqueous acid as explained above, or alternatively they can be converted to any desired pharmaceutically acceptable salt by double decomposition reactions involving the anion or cation, for example by ion-exchange procedures .

Moreover, apart from their usefulness in pharmaceutical applications, the salts are useful as characterizing or identifying derivatives of the free bases or free acids or in isolation or purification procedures. Like all of the salts, such characterization or purification salt derivatives can, - 29 - if desired, be used to regenerate the pharmaceutically acceptable free bases or free acids by reaction of the salts with aqueous base or aqueous acid, or alternatively they can be converted to a pharmaceutically acceptable salt by, for example, ion-exchange procedures.

The novel feature of the compounds then resides in the concept of the 2-saccharinylmethyl aryi carboxylates of formula J_ and not in any particular acid or base moiety or aci½ anion or base cation associated with the salt forms of the compounds.

The compounds of formulas I and VI of the invention can be prepared for pharmaceutical use by incorporating them in unit dosage form as tablets or capsules for- oral administration either alone or in combination with suitable adjuvants such as calcium carbonate, starch, lactose, talc, magnesium stearate, gum acacia and the like. Still further, the compounds can be formulated for oral, parenteral or aerosol inhalation administration either in aqueous solutions of water soluble salts of the compounds or in aqueous alcohol, glycol or oil solutions or oil-water emulsions in the same manner as conventional medicinal substances are prepared.

The percentages of active component in such compositions may be varied so that a suitable dosage is obtained. The dosage administered to a particular patient is variable, depending upon the clinician's judgment using as criteria: the route of administration, the duration of treatment, the size and physical condition of the patient, the potency of the active component and the patient's response thereto. An effective dosage amount: of the active component: can thus only be determined by the clinician after a consideration of ail cri-eria and using his best: judgment: on the patient's behalf. - 30 - The molecular structures of the compounds of the invention were assigned on the basis of study of their infrared and NMR spectra. The structures were confirmed by the correspondence between calculated and found values for elementary analyses for the elements or by analysis of the high-resolu ion mass spectra.

The following examples will further illustrate the invention without, however, limiting it thereto. All melting points are uncorrected.

The following description may include matter which is not claimed, but is retained herein for the sake of completeness.

Exemolarv Disclosure - 31 - Preparation of Starting Materials Prepara ion 3, Powdered potassium hydroxide (7.4 g, 0.132 mol) was admixed with dimethyl sulfoxide (DMSO) (100 ml), and the mixture was stirred for 5 minutes. 6-Methylanthranilic acid (10.0 g, 0.066 mol) was then added to the mixture and iodomethane (4.52 ml, 0.073 mol) added dropwise. The reaction mixture was stirred for 30 minutes at room temperature, then diluted with 250 ml of ether, washed with water (3 x 100 ml) , dried over magnesium sulfate and concentrated. The crude product was filtered through a pad of flash grade (32-63) silica gel and eluted with 1:9 ether rhexane to afford 4.23 g (39%) of methyl 6-methylanthranilate as an oil.

The methyl 6-methylanthranilate so prepared (4.23 g, 0.026 mol) was dissolved in 25 ml of acetic acid and the solution cooled to 0°C. Concentrated hydrochloric acid (45 ml) was added to produce a tan slurry. A solution of 1.89 g (0.027 mol) of sodium nitrite in 8 ml water was added dropwise with stirring, the resulting orange solution was stirred at 0°C for 1 hour and then added in 6 portions to a mixture of 2.18 g (0.013 mol) of cupric chloride dihydrate and sulfur dioxide (6.3 g) in 33 ml of acetic acid and 6 ml of water at 0°C. The dark green solution was stirred at room temperature overnight, poured into 300 ml of ice-water, and the solid which separated was collected and dried by suction to provide 1.11 g of methyl 2-chlorosulfonyl-6-methylbenzoate which was immediately added to 100 ml of ice cold ammonium hydroxide and stirred at room temperature overnight. The solution was acidified to pH 1 with concentrated hydrochloric acid, and the resulting precipitate was collected and air- - 32 - dried to provide 729 mg (12%) of 4-methylsaccharin . mp 224-226°C. Λ mixture of 1.0 g (0.005 mol) of 4-methylsaccharin, 0.33 g (0.001 mol) of ΤΒΛΒ and 1.2 g (0.0075 mol) of chloromethyl phenyl sulfide in 25 ml of toluene was heated under reflux for about sixteen hours and then cooled, diluted with ethyl acetate and the solution washed with aqueous bicarbonate and water. The organic layer was dried and taken to dryness to give 0.74 g of 2-phenylthiomethyl-4-methylsaccharin .

The latter (0.74 g, 0.002 mol) was dissolved in 25 ml of MDC and the solution treated dropwise over a period of about two hours with stirring with a solution of 0.47 g (0.003 mol) of sulfuryl chloride in MDC and the reaction mixture taken to dryness. The yellow residual solid was triturated with hexane and filtered and dried to give 0.46 g of 2-chloro-methyl-4-methyl saccharin as a pale yellow solid.

Preparation 2 Using the procedure described above in Preparation 1, 5.0 g (0.029 mol) of 6-chloroanthranilic acid and 2.75 ml (0.044 mol) of iodomethane were reacted in the presence of 4.08 g (0.073 mol) of powdered potassium hydroxide to give 4.22 g (70%) of methyl 6-chloroanthranilate as an oil. 4-Chlorosaccharin was prepared by the same method as used for the preparation of 4-methylsaccharin using 4.22 g (0.023 mol) of methyl 6-chloroanthranilate in 22 ml of acetic acid and 40 ml of concentrated hydrochloric acid and 1.60 g (0.024 mol) of sodium nitrite in 7 ml of water to prepare the diazonium salt which was added to 1.93 g (0.011 mol) of cupric chloride dihydrate and 6.5 g of sulfur dioxide in 30 ml of acotic acid and 5 ml of water. The resulting methyl 2-chlorosul£onyl-6-cl orobcnzoate was trented with 150 ml - 33 - of ammonium hydroxide as described above to afford 3.07 g (62%) of 4-chlorosaccharin as a pale yellow solid, mp 245-246°C. 2-Hvdroxvmethvl-4-chlorosaccharin was prepared by heating a solution of 1.00 g (0.0046 mol) of 4-chlorosaccharin and 3.22 ml of aqueous 37% formalin in ethanol. All attempts to crystallize the viscous oily product resulted in decomposition to the starting material, and the product was thus used in the next step without characterization.

The crude 2-hydroxymethyl-4-chlorosaccharin so prepared (609 mg, 0.0025 mol) was admixed with 5 ml of diethylether, and 3 ml of thionyl chloride was added. The resulting mixture was heated to effect complete solution, stirred at room temperature overnight, diluted with 20 ml of ether and filtered through a pad of celite topped with sand and eluted with ether. Removal of the solvent afforded 430 mg of crude chloromethyl derivative. A portion (225 mg) was removed for further reactions. The remainder (205 mg) was flash chromatographed on silica gel and eluted with 40% ether/pentane to provide 137 mg of 2-chloromethyl-4-chlorosaccharin. mp 135-136°C.

Preparation 3A To a suspension of 6.0 g (0.03 mol) of cuprous iodide in 100 ml of THF was added 25 ml of dimethyl sulfide, and the resulting yellow solution was cooled to -78°C and treated dropwise with a solution of 23 ml (0.06 mol) of a 3.0 M solution of phenyl magnesium bromide in diethyl ether. The resulting pale yellow-orange solution was stirred at -78°C under nitrogen for one hour and then treated with 3.02 g (0.03mol) of 2-cyclohexenone in 10 ml of THF. The resulting mixture was allowed to warm to 0°C over a two hour period, recooled to -78°C, treated with 15 ml of - 34 - hexamethylphosphoramide, stirred for thirty minutes, treated with 8.0 g (0.09 mol) of methyl cyanoformate and allowed to warm to ambient temperature overnight . The reaction mixture was poured into 100 ml of 2N hydrochloric acid, and the organic phase was separated and the aqueous phase back-extracted with MDC . The combined organic extracts were taken to dryness in vacuo and the residue triturated with saturated ammonium chloride, then with water, then with brine and taken to dryness once again to give 3.2 g of methyl 2-phenvlcvclohexan-6-one carboxylate as an oil.

The latter (3.0 g, 0.013 mol), 4.8 g (0.039 mol) of benzyl mercaptan and 1.0 g of Amberlyst®-15 resin (Rohm and Haas) in chloroform was heated under reflux for twenty hours, the mixture treated with an additional 1.5 g of the resin and heated for an additional four hours. The mixture was then cooled to ambient temperature, filtered, the filtrate taken to dryness in vacuo, the residue triturated with hexane and the solid collected by filtration to give 0.85 g (19%) of a mixture of methyl 2-benzYlthio-6-phenylcyclohex-2-sns. carbg yjate, and methyl a-frensyJ-thio-S-phenvlcvclohex-l-ene carboxylate. 0.6 g (0.0018 mol) of which was heated with 2.0 g of 2, 3-dichloro-5, 6-dicyanobenzoquinone in 25 ml of toluene with stirring under nitrogen for twenty-four hours. The mixture was filtered through a pad of silica gel, eluting with2:l MDC:hexane, and the eluate was taken to dryness to give 0.3 g (67%) of methyl 2-benzvlthio-6-phenvlbenzoate .

The latter (0.52 g, 0.0016 mol) dissolved in 10 ml of MDC was diluted with 20 ml of acetic acid and 5 ml of water, the mixture cooled to -10°C, and chlorine gas was bubbled through the mixture until the exothermic reaction subsided. The mixture was then stirred for ten minutes and taken to dryness in vacuo to give 0.41 g - 35 - (85%) Of methvl 2-chlorosul onyl-6-phenylbenzoate which was dissolved in 10 ml of THF and added to 25 ml of a solution of concentrated ammonium hydroxide while cooling in an ice/acetone bath. The reaction mixture was extracted with MDC, the organic phase discarded, and the aqueous layer acidified to pH 1 with concentrated hydrochloric acid and extracted with MDC. The organic extracts, on washing with brine, drying and evaporation to dryness, afforded 0.33 g (97%) of 4-phenvlsaccharin .

Following a procedure similar to that described in Preparation 1, the latter (0.33 g, 0.0012 mol) was reacted with 0.3 g (0.0019 mol) of chloromethyl phenyl sulfide in 15 ml of toluene in the presence of 0.08 g (0.0025 mol) of TBAB and the product, 2-phenvlthiomethvl-4-phenvlsaccharin (0.48 g, 100%), treated with sulfuryl chloride in MDC to give 0.36 g (95%) of 2-chloromethyl-4-phenylsaccharin. pre arat on 3B To a suspension of anhydrous CuCN (2.16 g, 0.025 mol) in anhydrous ether (100 mL) at -78°C was added tert butyllithium (29.0 mL of 1.7 M solution in pentane, 0.05 mol). After being stirred at -78°C for 1 hr and at -45°C for 30 minutes, the reaction mixture was recooled to -78°C. A solution of cyclohexenone (2.4 g, 0.025 mol) in ether (25 mL) was added and stirring continued for 15 minutes at -78°C and at -45°C for 30 minutes. The resulting mixture was recooled to -78°C, and HMPA (10 mL) in ether (25 mL) was added. After 5 min, methyl cyanoformate (2.55 g, 0.03 mol) in ether (25 mL) was added and the reaction warmed to 0°C over a 2 hr period. The resulting mixture was quenched with 2N HC1 (100 mL) , the layers were separated, and the organic phase was washed with saturated NH4CI solution (3 x 50 mL) , water (2 x 50 mL) , brine (1 x 50 mL) and dried ( a2S04) . Removal of the solvent in vacuo and - 36 - purification by Kugelrohr distillation (bath temperature 100-115°C at 0.6 mm) afforded 4.7 g (88%) of methyl 2- (1. l-dimethvlethyl>cynlohexan-6-one-carboxvlate.

The cyclohexanone (4.6 g, 0.022 mol) was mixed 5 with benzylmercaptan (2.95 g, 0.024 mol) and the acidic clay montmorillonite, KSF (7.5 g) in anhydrous toluene (7.5 mL) . The mixture was refluxed under nitrogen with azeotropic removal of water for 6 hr, cooled to room temperature and let stand overnight. The solids were 10 filtered off and washed with ether. The combined filtrate was washed with 10% Na2C03, water, brine and dried. Removal of the solvent in vacuo and purification of the residue by flash chromatography on silica gel (10% ether in hexanes) gave 4.4 g (66% of a mixture of 15 methvl 2-benzvlthio-6- ( 1.1-dimethvlethyl ) cvclohex-2-ene carboxyJ-ate and 2-benzylthio-6- (1.1- riimethvlethv ) cvclohex-l-ene carboxvlate . which was stirred with DDQ (17.5 g, 0.077 mol) in toluene (50 mL) for 16 hr. The red reaction mixture was filtered 2o through a 15 cm pad of silica gel, eluting with 6:3:1 hexanes :MDC : ether (1000 mL) . The eluents were washed with 10% NaOH solution, water, brine and dried. Removal of the solvent in vacuo and purification by chromatography on silica gel (5% ether in hexanes) gave 25 1.6 g (40%) of methvl 2-benzvlthio-6- Π .1 - dimethyl! benzoate.

The benzylthiobenzoate (1.3g, 0.004 mol) dissolved in DC (5 mL) was diluted with acetic acid (25 mL) and water (2 mL) , the mixture cooled to -10°C, and jQ chlorine gas was bubbled until the exothermic reaction subsided, the mixture was then stirred for 10 minutes and taken to dryness in vacuo. Purification of the residue by flash chromatography on silica gel (1:1 hexanes:MDC) gave 0.8 g (67%) of methyl 2- ,r h orosulfonyl-6- (1.1-dimethvlethvl ) benzoat e . which was - 37 - dissolved in THF (5 mL) and added to a solution of concentrated ammonium hydroxide (25 mL) while cooling in an ice/acetone bath. After stirring at room temperature for 16 hr, the reaction mixture was concentrated in 5 vacuo and acidified to pH 1 with 2N HC1. The separated solids were collected by filtration and cystallized from ether to give 0.64 g (95%) of 4- (1.1- dimethvlethvl) saccharin, mp 185-187°C.

The 4- (1, 1-dimethylethyl) saccharin (0.025 g )0 1.0 mmol) was mixed with chloromothyl phenyl milfldo (0.25 g, 1.5 mmol) and tetrabutyl ammonium bromide (0.2 g, 0.6 mmol) in toluene (25 mL) and refluxed under nitrogen for 16 hr. The resulting mixture was cooled to room temperature, evaporated to dryness and purified by 15 chromatography on silica gel (80%) MDC in hexanes) to give 0.35 g (98%) of 2-phenylthiomethyl-4- (1.1- dimethylethyl) saccharin, which was treated with sulfuryl chloride (0.25 g, 1.8 mmol) in MDC to give 0.21g (75%) of 2-chloromethyl-4- ( 1.1-dimethylethyl) saccharin . 0 preparat on 4 A mixture of 3.22 g (0.012 mol) of 4- bromosaccharin [Japanese Pat. Publcn. 58/79,034, C.A. 100. 7773w (1984)], 1.63 g (0.015 mol) of potassium t-butoxide, 0.39 g (0.0012 mol) 5 of TBAB and 3.0 ml (0.022 mol) of chloromethyl phenyl sulfide in 100 ml of toluene was heated under reflux under a nitrogen atmosphere for eight hours and then stirred at ambient temperature for about sixteen hours. The reaction mixture was then diluted with ethyl 30 acetate, and the organic layer was washed with dilute potassium carbonate, water and brine, dried over magnesium sulfate and taken to dryness in vacuo . The residual solid was recrystallized from toluene-hexane to give 3.86 g (84%) of 4-bromo-2-phenyl-,r thiometh 1 saccharin, mp 174.5-178°C. - 38 - To a solution of the latter (3.27 g, 0.0085 mol) in 85 ml of MDC was added, dropwise with stirring, 1.02 ml (0.0127 mol) of sulfuryl chloride. The mixture was stirred at ambient temperature for an hour and a half, concentrated A& vacuo and the residue triturated with hexane and filtered to give 2.61 g of crude product which was recrystallized from toluene-hexane to give 2.24 g (85%) 2-nhloromethvl-4-bromosaccharin. mp 157- 159°C.

Preparation 5 To a solution of 8.0 ml (0.053 mol) of tetra-methylethylenediamine (TMEDA) in 350 ml of THF at -70°C was added 42 ml (0.055 mol) of a 1.3 solution of s-butyl lithium in cyclohexane and the mixture was stirred for fifteen minutes. To the solution was added dropwise with stirring a solution of 10.36 g (0.050 mol) of 2-methoxy-N,N-diethylbenzamide in 150 ml of THF while maintaining the temperature at -60°C or below. After stirring for 20 minutes sulfur dioxide was bubbled into the reaction mixture, keeping the reaction temperature below -50°C, until the reaction mixture was acid to wet litmus paper. The mixture was stirred at ambient temperature for two hours, diluted with 450 ml of hexane, and the solid material which had separated was collected, dissolved in 200 ml of water and the mixture treated with 65 g of sodium acetate and 21.5 g (0.19 mol) of hydroxylamine-O-sulfonic acid in portions with stirring. The white solid which separated was collected and dried to give 7.04 g (49%) of 2-aminosulfonyl-6-methoxy- . N-diethvlbenzamide . mp 190-194.5°C.

A mixture of the product (4.3 g, 0.015 mol) in 75 ml of dioxane and 25 ml of concentrated hydrochloric acid was heated on a steam bath for 70 hours, then cooled, concentrated in vacuo, diluted with water and ice and rendered strongly basic with concentrated sodium - 39 - hydroxide. The mixture was washed with MDC, and the aqueous layer was acidified with dilute hydrochloric acid and extracted with MDC. The extracts were dried over magnesium sulfate and taken to dryness to give 1.29 g (40%) of 4-methoxvsaccharin . In an alternative, and preferred, procedure, cyclization of 2-aminosulfonyl-6-methoxy-N, N-diethylbenzamide to 4-methoxysaccharin in 65% yield was carried out in refluxing glacial acetic acid for six and a half hours.

Following a procedure similar to that described in Preparation 4 above, 1.14 g (0.0053 mol) of the latter was reacted with 1.31 ml (0.0097 mol) of chloromethyl phenylsulfide in toluene in the presence of 0.72 g (0.0064 mol) of potassium t-butoxide and 174 mg (0.00054 mol) of tetrabutylammoniuiti bromide to give 1.23 g (69%) of ^-metho y-2-p e l pm¾ hylsaQcharj,n, mp 152.5-154.5°C (from ethyl acetate-hexane) , 1.02 g (0.003 mol) of which was treated with 0.36 ml (0.0045 mol) of sulfuryl chloride in MDC to give 282 mg (36%) of 2=. chloromethyl-4-methoxv-sac harin. mp 169-174°C.

Preparation 6A To a solution of 4.74 ml (0.031 mol) of tetramethylethylenediamine in 300 ml of THF (passed through alumina prior to use) was added 5.8 g (0.03 mol) of 2-ethyl-N,N-diethyl-7benzamide. The solution was cooled to -78°C and treated with 34.9 ml (0.031 mol) of a 0.9 M solution of s-butyl lithium in cyclohexane.

When addition was complete, the mixture was stirred for twenty minutes and then treated with a solution of 3.2 ml (0.04 mol) of ethyl iodide while maintaining the temperature at -78°C. The temperature was then allowed to rise to ambient temperature and the mixture stirred for about sixteen hours and then poured into water. The resulting oil was separated and chromatographed on silica gel, eluting with 10% ethyl acetate/hexane to - 40 - give 2.86 g (43%) of 2-sec . -butyl-N. N-diethv benzamide as a yellow oil.

Following a procedure similar to that described in Preparation 5 above, the latter (10.45 g, 0.045 mol), dissolved in 70 ml of THF, was added to a solution of 39.2 ml (0.047 mol) of a 1.2 M solution of s-butyl lithium in cyclohexane and .1 ml (0.047 mol) of tetramethylethylene-diamine in 250 ml of THF while maintaining the temperature at -78°C. When addition was complete the mixture was stirred for an additional one half hour at -78°C and then treated with sulfur dioxide at -70°C and then allowed to warm to room temperature. The mixture was taken to dryness n vacuo, and the residue was dissolved in water and added with stirring to a cold solution of 15.2 g (0.134 mol) of hydroxylamine-O-sulfonic acid and 15.4 ml (0.134 mol) of 35% sodium hydroxide to give 10.1 g (72%) of 2=. aminosulfonvl-6-sec.-butvl-N.N-diethvlbenzamide.

The latter (6.83 g, 0.22 mol) was dissolved in 100 ml of glacial acetic acid and the solution heated under reflux for thirteen hours and then taken to dryness. The residue was triturated with diethyl ether and collected by filtration to give 5.7 g (83%) of the diethylammonium salt of 4-sec .-butvlsaccharin .

The latter (3.0 g, 0.0096 mol), on reaction with 1.13 ml (0.012 mol) of chloromethyl phenyl sulfide in toluene, afforded 3.47 g (100%) of 2sz phenylthiomethvl-4-sec .-butvlsaccharin .

Reaction of the latter (3.2 g, 0.0097 mol) with 2.3 ml (0.029 mol) of sulfuryl chloride in 20 ml of MDC afforded 2.4 g (87%) of 2-chloromethyl-4-sec . -butvlsaccharin.

Preparation 6B By a procedure analogous to that described for Preparation 6A, 9.2 g (32.9 mmol) of 3, 4 , dimethoxy-2- - 41 - propyl-N, N-diethylbenzamide was reacted with sulfur dioxide and 5.6 g (49.4 mntol) of hydroxylamine-O-sulfonic acid to provide 7.4 g (63%) of 2-aminosulfonyl-4.5-dimethoxY-6-propyl-N.N-dimethvlbenzamide which was cyclized in quantitative yield in acetic acid and phenylthiomethylated with 1.42 mL (15 mmol) of chloromethyl phenyl sulfide to provide 4.07 g of 5. -dimethoxy-2-phenylthiomethyl-4-proDvlsaccharin.

Reaction of 3.59 g (8.8 mmol) of the phenylthioether with 2.12 mL (26.4 mmol) sulfuryl chloride provided 2.84 g (97%) of 2-chloromethyl-5.6-dimethoxv-4- rQ yisacc rin.

The 3, 4-dimethoxy-2-propyl-N, -diethylbenzamide was obtained by the following procedure: To a solution of .216 moles of n-butyllithium in 250 mL of ether at ambient temperature was added dropwise 138.2 g (0.216. mol) of veratrol in 100 mL of ether and 32.6 mL (0.216 mol) of TMEDA. The reaction was stirred at ambient temperature 14 hours and 21.9 mL (0.225 mol) of n-propyl iodide was added with cooling. The reaction was stirred 1 hour at RT and worked up with aqueous IN HC1 to give 14 g (36%) of 2.3-dAme hPMybenzene ro ane which was brominated with 14.52 g (81.6 mmol) of N-bromosuccinimide on 36 g of Kieselgel in 400 mL of CCI4 according to the method of Hisatoshi et al. fBull. £k≤m. JISE.22., 591-593 (1989)] to give 19.6 g (98%) of 6-bromo-2.3-dimethoxvbenzenepropropane .

The bromobenzene (1 .2g, 54.8 mmol) was dissolved in 200 mL ether, cooled to -78°, and 25.2 mL (63 mmol) of 2.5 N n-butyllithium in hexane was added. The reaction was warmed to 0°, held for an hour, and cooled to -70°, and 9 mL (71.2 mmol) of diethyl carbamyl chloride was added. The reaction was allowed to come to RT and was quenched with saturated ammonium chloride. - 42 - After extraction and drying, the product was crystallized from hexane to provide 9.5 g (62%) of 3.4-dimethoxv-2-propvl-N.N-diethvlbenzamide. mp 65-67°.

Preparation 6C By a process analogous to that of preparation 6B, 10.75 g (30 mmol) of 6-aminosulfonyl-3, 4-dimethoxy-2-isopropyl-N,N-diethylbenzamide was cyclized'to provide 6.43 g of 5.6-dimethoxv-4-isopropvl saccharin (mp 186- 188 from ether-hexane), 5 g (17.5 mmol) of which was phenylthiomethylated with 2.48 mL (26.3 mmol) of phenylthiomethylchloride according to the procedure of Preparation 5, and chlorinated with 3 equivalents of sulfuryl chloride to provide an 85% yield of 2-ch oromethy -5.6-dimethoxy-4-isopropvlsaccharin . mp 117-119° from ethyl acetate-hexane .

The requisite benzamide was obtained from 2,3-dimethoxy-a-methylbenzeneethane by bromination followed by carbamylation as in Preparation 6B, to provide the intermediate 3, 4-dimethoxy-2-isopropyl-N, N-diethylbenzamide . A solution of 66 mL of 0.96M sec-butyllithium was added to 16.1 g (57.6 mmol) of the benzamide in 400 mL of THF at -78° under nitrogen.

After stirring 2 hours the orange anion was cannulated into excess sulfur dioxide at -60°. The reaction was allowed to come to room temperature and stirred for 18 hrs to remove SO2. Ten milliliters of sulfuryl chloride was added at 0° and the reaction was stripped. The sulfonyl chloride was extracted into EtOAc-ether, washed with water, dried and stripped. The residue was dissolved in 80 mL of THF and 17 mL of cone. NH4OH was added at 0°. The reaction was stirred briefly at RT, stripped, and triturated in 2:1 ether-hexane to provide 12.89 g (62%) of 6-aminosulfonyl-3.4-dimethoxy-2-isopropyl- . N-diethvlbenzamide . mp 138-140°. - 43.- Preparation 7 To a solution of 9.3 ml (0.058 mol) of tetramethylethylenediamine in 340 ml of THF at -78°C was added 52 ml of a 1.1 M solution (0.057 mol) of s-butyl lithium in cyclohexane. The solution was then treated with a solution of 11.37 g (0.052 mol) of 2-propyl-N,N-diethylbenzamide in 75 ml of THF at -78°C and the solution stirred for fifteen minutes and then treated with a solution of 8.3 ml (0.104 mol) of ethyl iodide in THF. The solution was stirred for an hour and a half at -78°C and then quenched by the addition of saturated ammonium chloride added dropwise at -78°C.

The mixture was then allowed to warm to ambient temperature, diluted with diethyl ether, washed first with dilute hydrochloric acid, then with water, then with saturated sodium bicarbonate, then with brine, dried and taken to dryness to give 12.91 g of crude product which was chromatographed on silica gel, eluting with 10% ethyl acetate/hexane to give 3.23 g (25%) of 2=. t3-pentvli -N.N-diethylbenzamide as a yellow oil.

Following a procedure similar to that described in Preparation 5 above, the latter (3.05 g, 0.0115 mol) in THF was reacted with 10.5 ml (0.126 mol) of a 1.2 M solution of s-butyl lithium in cyclohexane in the presence of 2.1 ml (0.014 mol) of tetramethylethylenediamine. The resulting lithium salt was then reacted first with sulfur dioxide and then with sodium hydroxylamine-O-sulfonate to give 1.97 g (52%) of 2-aminosulfonyl-6-(3-pentvl)-N.N-diethvlbenzamide as pale yellow crystals, mp 118-120°C (soft 102°), 1.84 g (0.0056 mol) of which was cyclized in 22 ml of refluxing glacial acetic acid to give 1.28 g (70%) of the diethvlammonium salt of 4- (3-pent l ) sacchari n . mp 107.5- 109.5°C. - 44 - The latter (0.0037 mol), on reaction with 0.74 ml (0.0055 mol) of chloromethyl phenyl sulfide in the presence of 116 mg (0.0004 mol) of TBAB in 45 ml of toluene, afforded 1.93 g of 2-phenylthiomethyl-4- (3-pen yl) saccharin as a pale yellow oil, 1.93 g (0.0037 mol) of which, on reaction with 0.59 ml (0.0073 mol) of sulfuryl chloride in 37 ml of MDC, afforded 1.2 g of Z. chloromethyl-4- (3-pentvli saccharin as a pale yellow oil.

Pre a at on 8 A solution of 50.0 g (0.27 mol) of 2,4-dimethoxybenzoic acid in 60 ml (98.0 g, 0.82 mol) of thionyl chloride was heated under reflux for three hours, then cooled, and the excess thionyl chloride distilled off. The resulting 2, 4-dimethoxybenzoyl chloride was dissolved in 150 ml of MDC and the solution treated with a solution of 68 ml (48 g, 0.66 mol) of diethylamine in 500 ml of MDC, cooled to 0°C. When addition was complete the mixture was stirred for fifteen hours at ambient temperature, then washed with saturated sodium bicarbonate, water and brine and taken to dryness and the residue distilled in vacuo to give 44.78 g (69%) of 2. -dimethoxy- . N-diethvlbenzamide . b.p. 155-163°C/0.4 mm.

Following a procedure similar to that described in Preparation 5 above, 10.0 g (0.042 mol) of the product in 250 ml of THF was reacted with 40.57 ml of a 1.1 M solution (0.044mol) of s-butyl lithium in cyclohexane and 6.35 ml (0.042 mol) of tetramethylethylenediamine in THF. The resulting lithium salt was then reacted first with about 40 ml of sulfur dioxide and then with an aqueous solution (0.13 mol) of sodium hydroxylamine-O-sulfonate to give 8.26 g of 2-aminosulfonvl-4.6-dime hoxv-N.N-diethylbenzamide. 7.0 g of which (0.022 mol) was cyclized in 80 ml of refluxing glacial acetic acid to give 6.6 g (94%) of the - 45 - diethvlammonium salt of 4.6-dimethoxv-saccharin which was used as such in the next step without further purification.

The latter (6.0 g, 0.019 mol), on reaction with 3.82 ml (0.028 mol) of chloromethyl phenyl sulfide in the presence of 0.611 g (0.0019 mol) of TBAB in 200 ml of toluene, afforded 6.2 g (89%) of Z phenylthioniethyl-4.6-dimethoxvsaccharin .5.82 g of which (0.016 mol), on reaction with 3.23 g (0.0019 mol) of sulfuryl chloride in 100 ml of MDC, afforded 4.63 g (100%) of 2-chloromethyl- .6-dimethoxysaccharin. m.p. 185-187°C.

Preparation 9A - 9G Following a procedure similar to that described above in Preparation 5, substituting for the 2-methoxy-N,N-diethylbenzamide used therein an appropriate 2-R4-R^-substituted-N,N-diethylbenzamide, the following 2-halomethyl-4-R4-R5-saccharins listed in TABLE A were prepared via the corresponding 2-phenylthiomethylsaccharins . Wherever available, the melting point, recrystallization solvent and yield are given for each of the 2-unsubstituted saccharins, the 2-phenylthiomethylsaccharins and the 2-chloromethylsaccharins in columns headed "mp/Solv." and "Yield". In all instances, the intermediate 2-phenylthiomethylsaccharins were used directly in the subsequent step without further characterization or purification.

TABLE A Sacc 2-C6H5SCH2-Sacc 2-ClCH2-Sacc Prep mp/Solv Yield mp/Solv £iej__i mp/Solv Hold 9A H 260-262 93 100 158.0-160.0 51 7-Cl i-PrOH 9B CH(CH3)2 177.0-178.0 100 93.0-96.0 100 H MeOH i-PrOH-Cyc hex 9C CH30 (a) 64 100 190.0-192.0 76 5-CH3O 9D COOCH3 (b) 76 65 186.0-187.0 H EtOAc-hex 9E C2H5O (a) 96 95 139.0-140.0 97 H 9F (CH3)2CHO 87 75 142.5-143.5 94 H 9G C2H5 i-PrOH 67 52 99 5,7-(CH30)2 (a) Isolated and used in the next step as the diethylammonium salt. (b) The 2-unsubstituted-saccharin was prepared by cyclization of dimethyl 3- aminosulfonylphthalate in methanol in the presence of a molar equivalent of sodium methoxide. The phthalate ester was prepared by diazotization of dimethyl 3-aminophthalate, decomposition of the diazonium salt with sulfur dioxide in the presence of cupric chloride and reaction of the resulting dimethyl 2-chlorosulfonylphthalate with ammonia. (84% yield overall) . - 47 - pre aration 10 Following a procedure similar to that described in Preparation 2, reaction of 18.3 g (0.1 mol) of saccharin with 70 ml of 37% formalin in ethanol afforded 3.58 g (70%) of 2-hydroxymethylsaccharin . The latter (25 g, 0.117 mol) was reacted with 63.3 g (0.234 mol) of phosphorus tribromide in diethyl ether to give 29.8 g (92%) of 2-bromomethylsaccharin . mp 155-157°C.

Pre ara ion IX To a solution of 4 g (0.0175 mol) of 6-nitrosaccharin in 240 ml of ethanol was added 4.4 g (0.0175 mol) of thallium ethoxide, and the mixture was allowed to stand at room temperature for one hour, cooled for about 16 hours and the precipitated solid collected and dried to give 7.6 g (100%) of the thallium salt of 6-nitrosaccharin . The product was suspended in 50 ml of DMF and the mixture treated with 3.07 g (0.0194 mol) of chloromethyl phenyl sulfide, the mixture warmed at about 63°C for five hours, allowed to stand at ambient temperature for about 16 hours, and then poured into ice water. The crude product, obtained by filtration, was stirred in DC and filtered to remove thallium salts. The filtrate was freed of solvent, and the resultant pale yellow solid was sonicated with warm ethanol and once again collected and dried to give 4.6 g (75%) of 6-nitro-2-phenvlthiomethvlsaccharin. mp 161- 163°C. The latter, on reaction with sulfuryl chloride in MDC using the procedure described above in Preparation 4, afforded 3.7 g of 2-chloromethyl-6-nitrosaccharin. prepar ion ¾2 A solution of 49.8 g (0.199 mol) of 2-hydroxy-5- (1, 1, 3, 3-tetramethylbutyl) benzoic acid in 200 ml of methanol was heated to 50°C and then treated dropwise with about 80 g of sulfuric acid at a rate to maintain - 48 - the reaction under reflux. The reaction mixture was heated under reflux for an additional 11 hours, then cooled and partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, then with brine, dried over sodium sulfate and taken to dryness to give 48.6 g (92%) of methyl 2-hydroxy-5- (1.1.3.3-tetramethvlbutvl ) benzoate .

The latter dissolved in 250 ml of DMF was treated first with 40.4 g (0.36 mol) of 1,4-diazabicyclo [2.2.2]octane followed by 33.4 g (0.27 mol) of Ν,Ν-dimethylchlorothiocarbamate and 100 ml of DMF. The reaction mixture was heated at 45°C for about eight hours, cooled, poured into ice/water and concentrated hydrochloric acid and then extracted with ethyl acetate. The combined organic extracts were washed with dilute hydrochloric acid, then with sodium bicarbonate and then with brine, dried and taken to dryness to give 48.2 g (76%) of methyl 2- (N.N-dimethvlthiocarbamvloxv¾ -5-f 1.1.3.3-tetramethvlbutvl¾ benzoate which was heated at 220°C for 15 hours, then cooled, dissolved in toluene and chromatographed on silica, eluting with 1:9 ethyl acetate: toluene, to give 3.6 g (14%) of methyl 2-(N.N-dimethylcarbarnylthio) -5- ( 1.1.3.3-tetramethylbutyll benzoate.

A solution of the latter (0.025 mol) in 40 ml of MDC was treated, with stirring, with 80 ml of glacial acetic acid, followed by 16 ml of water. The reaction mixture was cooled to 0°C, and chlorine was bubbled through the reaction mixture for about five minutes while maintaining the temperature between 5 and 24°C. The reaction was stirred for an additional 30 minutes, concentrated .in vacuo, and the remaining solution poured into ice water. Extraction of the mixture with ethyl acetate and isolation of the product from the combined - 49 - organic extracts afforded 6.8 g (78%) of methyl 2-chlorosulfonyl-5- .1.3.3-tetramethvlbutvl¾ benzoate .

The product (9.0 g, 0.026 mol) was dissolved in THF and added to 100 ml of concentrated ammonium hydroxide with cooling in an ice bath. The resulting solution was stirred for about 16 hours, then concentrated in vacuo and the concentrated solution acidified to pH 3 with concentrated hydrochloric acid. The mixture was stirred for several hours, and the separated solid collected, washed with water and dried to give 9.0 g of 5- (1.1.3.3-tetramethvlbuty1i saccharin. mp 213-215°C.

Following a procedure similar to that described in Preparation 11, 9.0 g (0.30 mol) of the product was reacted with thallium ethoxide in ethanol and the resulting thallium salt reacted with 3.33 g (0.021 mol) of chloromethyl phenylsulfide in DMF to give 5.76 g (66%) of 2-phenylthiomethyl-5- (1.1.3.3-tetramethylbutyll saccharin. 3.3 g (0.007 mol) of which was treated with 0.944 g of sulfuryl chloride in MDC to give 1 g (41%) of 2-chloromethyl-5- (I, I, 3, 3- et amethyl-butvl) saccharin. preparation 13 Following a procedure similar to that described in Preparation 12 above, 15.5 g (0.086 mol) of ethyl 2-hydroxy-6-methylbenzoate was reacted with 15.9 g (0.129 mol) of Ν,Ν-dimethylchlorothiocarbamate in the presence of 19.3 g (0.172 mol) of 1,4-diazabicyclo[2.2.2]octane in DMF to give 22.1 g (96%) of ethyl 2- ( . N-dimethylthiocarbamvloxy¾ -6-methvlbenzoa fi which was heated at 220°C for about 10 hours. The product was purified by chromatography on silica gel in MDC to give ethvl 2- (N . N-dimethylcarbamvl hio¾ -6-methylbenzoate as a red-brown oil. - 50 - A solution of the latter (22.6 g, 0.0844 mol) in 170 ml of MDC was treated with 340 ml of glacial acetic acid and 68 ml of water while cooling in an ice/acetone bath, and chlorine was bubbled through the reaction mixture for 10-15 minutes.The reaction vessel was evacuated to remove excess chlorine and MDC and the mixture poured into water and partitioned between MDC and water. The organic layer, on drying and evaporation to dryness, afforded 19 g of ethyl 2-chlorosulfonvl-6-methylbenzoate. 5 g (0.019 mol) of which was reacted with concentrated ammonium hydroxide in THF to give 6.1 g (67%) of 4-methylsaccharin .

Following a procedure similar to that described in Preparation 11 above, the product (10.1 g, 0.0512 mol) was converted to the thallium salt by reaction with 12.8 g (0.0512 mol) of thallium ethoxide in ethanol and the thallium salt reacted with 6.7 g (0.0427 mol) of chloromethyl phenyl sulfide in DMF to give 6.85 g (50%) of 2-phenylthiomethYl-4-methylsaccharin.

Reaction of the latter (6.7 g, 0.021 mol) with sulfuryl chloride in MDC afforded 4.9 g (95%) of Z. chlpromethyl-4-methylsa^char;in .

Prep ration J,4A A mixture of 75 g (0.36 mol) of 3,3-dithiobispropionic acid, 102 ml of thionyl chloride and a catalytic amount of pyridine was stirred for about 24 hours and then evaporated to dryness in vacuo . The residue was treated with MDC and evaporated to dryness again to remove residual thionyl chloride and pyridine to give 87 g (98%) of the corresponding bis acid chloride♦ 44.8 g (0.18 mol) of which was dissolved in THF and added dropwise to a solution of 77.16 g (0.72 mol) of benzylamine in THF. The mixture was stirred for two hours at 40-45°C, cooled and the precipitated solid - 51 - collected, washed with water and dried to give 59 g (84%) of 3, 3-dAthiPkis-prppipnic ac d , '-dibenzvlcarboxamide . mp 162-165°C.

Reaction of 7.0 g (0.018 mol) of the latter with 10.25 g (0.076 mol) of sulfuryl chloride in MDC gave a mixture of 2-benzyl-2H-isothiazol-3-one and 5-chloro-2-benzyl-2H-isothiazol-3-one which were largely separated from one another by sonication in MDC (which solubilized most of the former) . The insoluble material was collected by filtration and chromatographed on silica gel with MDC. There was thus obtained 5-chloro-2-benzvl-2H-isothiazol-3-one. mp 58-68°C.

A solution of 10 g (0.044 mol) of the latter in MDC was cooled to 0°C and the solution treated with 7.6 g (0.044 mol) of 3-chloroperbenzoic acid, the mixture stirred for 10 minutes and then treated with a second 7.6 g portion of the perbenzoic acid. The reaction mixture was filtered, the filter washed with MDC and the filtrate washed with saturated sodium bicarbonate, then with brine, dried over sodium sulfate and taken to dryness and the residue chromatographed in MDC on silica gel, the product being eluted with 50:50 hexane:MDC, to give 7.15 g (46%) of 5-chloro-2-benzvl-2H-isothiazol-3-»one-l-oxide .

A solution of 1.1 g (0.0045 mol) of the latter in 8 ml of benzene was treated with 0.55 g (0.0051 mol) of 2-methoxyfuran and the solution heated in a pressure bottle at 70°C for 1.5 hours and then cooled and the solid collected, washed with benzene and dried to give 2-benzvl-7-hvdroxv-4-methoxvbenzisothiazol-3~one-l-oxide. mp 235-237°C.

A mixture of the product (1.85 g, 0.006 mol), 2.48 g (0.018 mol) of potassium carbonate and 1.70 g (0.012 mol) of methyl iodide in acetone was heated under reflux for 1.5 hours and then cooled and poured into - 52 - water. The solid which separated was collected by filtration, washed with water and dried to give 1.70 g (89%) of 2-benzyl- .7-dimethoxvbenzisothiazol-3-one-l-oxide. 1.13 g (0.0035 mol) of which was oxidized with 1.20 g (0.007 mol) of 3-chloroperbenzoic acid in MDC using the procedure described above to give 1.03 g (88%) of 2-benzyl- .7-dims hnxvsaccharin .

A mixture of 2.07 g (0.0062 mol) of the product, 1.37 g (0.02 mol) of ammonium formate and 1.5 g of 10% palladium-on-charcoal catalyst in 80 ml of methanol was heated under reflux for one hour, then cooled and filtered, and the filtrate taken to dryness to give 0.92 g (57%) of the ammonium salt of 4.7-dimethoxvsaccharin .

A solution of 1.11 g (0.0042 mol) of the ammonium salt was dissolved in DMF, 0.67 g (0.0042 mol) of chloromethyl phenyl sulfide was added, and the solution heated under reflux for eight hours and then cooled and poured into ice water. The solid which separated was collected, washed with water and dried to give 0.50 g (33%) of 2-phenvlthiomethvl-4.7-dimethoxysaccharin .

Reaction of the latter (0.5 g, 0.0013 mol) with sulfuryl chloride in MDC using the procedure described above in Preparation 4 afforded 0.22 g (58%) of 2-chloromethyl-4.7-dimethoxvsaccharin .

Preparations 14B and 14C Following a procedure similar to that described in Preparation 14A, other 2-chloromethylsaccharin derivatives were prepared as follows : Preparation. 14B Reaction of 5.8 g (0.024 mol) of 5-chloro-2-benzyl-2H-isothiazol-3-one-l-oxide with 3.76 g (0.0335 mol) of 2-ethoxyfuran afforded 3.05 g (40%) of 2-benzyl- - 53 - 4-ethoxv-7-hvdroxvbenzisothiazol-3-one-l-oxide. 5.7 g of which was reacted with 3.6 g (0.0197 mol) of 2- [2-methoxyethoxy] ethyl bromide in the presence of 4.95 g (0.0358 mol) of potassium carbonate in 125 ml of methyl ethyl ketone and 25 ml of DMF to give 7.0 g (93%) of 2-benzvl-4-ethoxv-7- Γ2- (2-methoxv-ethoxyl ethoxyl benzisothiazol-3-one-l-oxide. which was oxidized as before with 3-chloroperbenzoic acid in DC to give 2-benzvl-4-ethoxv-7- f2- (2-methoxyp1-hoxv¾ ethoxvl -saccharin. Debenzylation of 6.6 g (0.015 mol) of the latter with 3.34 g (0.053 mol) of ammonium formate in the presence of 6.4 g of 10% palladium-on-charcoal catalyst in methanol afforded the ammonium salt of 4-ethoxv-7- 12- <2-methoxv-ethoxy) ethoxvl saccharin, which was reacted with 2.38 g (0.015 mol) of chloromethyl phenyl sulfide in 100 mL of DMF to give 1.46 g (21%) of 2-phenylthiomethyl-4-ethoxy-7- Γ2- (2-methoxvethoxy) -ethoxyl saccharin, mp 73-75°C (from isopropanol) .

Treatment of 1.4 g (0.0029 mol) of the product with 0.4 o (0.0029 mol) of sulfurvl chloride in MDC afforded 1.16 q (100%¾ of 2-chloromethvl-4-ethoxv-7- 12-/2-methoxyethoxy) ethoxvl -saccharin .

Preparation 14C Reaction of 3.03 g (0.01 mol) of 2-benzyl-7-hydroxy-4-methoxybenzisothiazol-3-one-l-oxide (Preparation 14A) with 2.01 g (0.011 mol) of 2-(2-methoxyethoxy) ethyl bromide in methyl ethyl ketone in the presence of 2 g (0.015 mol) of potassium carbonate afforded 2.58 g (64%) of 2-benzyl-4-methoxy-7- Γ2- (2-methoxyethoxvl ethoxvl benzisothia-zol-3-one-l-oxide . which, on oxidation with 1.1 g (0.0063 mol) of 3-chloroperbenzoic acid in MDC, gave 2-benzyl-4-methoxy-7-12- (2-methoxyethoxy) ethoxyl saccharin . Debenzylation of 0.25 g (0.0006 mol) of the product with 0.13 g (0.0021 mol) of ammonium formate in methanol in the presence of - 54 - 0.25 g of 10% palladium-on-charcoal gave 0.21 g (100%) of the ammonium salt of 4-methoxv-7- f2- (2-methoxvethoxy) ethoxvl saccharin . Reaction of 1.4 g (0.004 mol) of the ammonium salt with 0.63 g (0.004 mol) of chloromethyl phenyl sulfide in DMF afforded 2. phenylthiomethvl-4-methoxy-7- Γ2- ( 2-methoxyethoxyi ethoxyl saccharin, which, on reaction with sulfuryl chloride in MDC, afforded 0.53 g (35%) of Zz. chloromethvl-4-methoxv-7- Γ2- (2-methoxvethoxv¾ ethoxv1 -saccharin.

Preparation 15 A solution of 1.89 g (0.011 mol) of diethylamino sulfur trifluoride (DAST) in 20 ml of MDC was added to a suspension of 2.13 g (0.01 mol) of 2-hydroxymethylsaccharxn in 25 ml of MDC while maintaining the reaction mixture at -78°C.

The reaction mixture was stirred at -78°C for one hour, the temperature allowed to slowly rise to ambient temperature, the mixture stirred for 16 hours and then poured into ice-water. The organic layer was separated and washed with water, dried over magnesium sulfate and taken to dryness to give 2.2 g of product which was recrystallized from ethyl acetate to give 1.6 g (74%) of 2-fluoromethvlsaccharin . mp 96-98°C.

Preparation 16A To a solution of 0.5 g (0.0025 mol) of 4-methyl-saccharin in THF cooled to -78°C by a dry ice/acetone bath was added, dropwise with stirring, a solution of 5.2 ml of a 1.3 M solution of s-butyl lithium in cyclohexane. The mixture was stirred an additional hour at -78°C and then treated with 0.16 ml (0.025 mol) of methyl iodide over a l l/2 hour period. The mixture was stirred for an hour and 45 minutes, quenched in 25 ml of IN hydrochloric acid, the reaction mixture rendered basic, the aqueous mixture extracted - 55 - with chloroform and then acidified and extracted with ethyl acetate. The combined organic extracts were washed with 10% sodium thiosulfate, then with brine, dried over sodium sulfate and taken to dryness to give a product, whose PMR spectrum indicated a mixture consisting of 74% of 4-ethylsaccharin and 21% of 4,7-dimethylsaccharin .

Following a procedure similar to that described in Preparation 4 above, the crude material (0.47 g, 0.0022 mol) was reacted with 0.24 ml (0.0028 mol) of chloromethyl phenylsulfide in toluene in the presence of tetrabutylammonium bromide, and the product chromatographed on silica gel, eluting with MDC, 5 ml fractions being collected. The first 420 ml of eluate were discarded. The next 20 fractions, on evaporation, afforded 0.07 g of material, predominantly 2-phenylthiomethyl-4, 7-dimethylsaccharin, which was set aside. The next 25 fractions afforded 0.37 g of 2-Dhenvlthiomethvl-4-ethylsaccharin. which was reacted with sulfuryl chloride in MDC to give 0.19 g (66%) of 2-chloromethyl-4-ethylsaccharin .

Preparation 16B Following a procedure similar to that described in Preparation 16A, 10 g (0.051 mol) of 4-methylsaccharin in THF was reacted with 86 ml (0.10 mol) of a 1.18 M solution of s-butyl lithium in cyclohexane and the resulting solution treated with 4.5 ml (0.050 mol) of ethyl iodide to give 10.15 g (89%) of 4-propylsaccharin. which, on reaction with 5.32 ml (0.056 mol) of chloromethyl phenyl sulfide in toluene in the presence of tetrabutylammonium bromide, afforded a crude mixture from which was isolated by flash chromatography on silica gel 2-phenylthiomethvl-4-propvlsaccharin as an oil, 1.8 g (0.0052 mol) of which, on reaction with 1.25 - 56 - ml (0.016 mol) of sulfuryl chloride in MDC, afforded 0.94 g (66%) of 2-chloromethvl-4-propvlsaccharin .

Preparation 16C A preferred alternative to preparation 16A is as follows : To a solution of 5.13 g (25 mmol) of N,N,2-triethylbenzamide in THF (50 mL) at -78° was added a solution of LDA (Aldrich 2.0M, 15.63 mL, 31.25 mmol) . The solution was warmed to -10°C with ice water over 1 hr, then cooled to -78°C with dry ice-acetone. TMSC1 (6.34 mL, 50 mmol) was added neat at -78°C and then reaction brought to room temperature after 1 hr. The reaction was quenched with saturated NH4CI and extracted with ether (2 x 100 mL) , dried over MgSO^, stripped and the residue distilled in a Kugelrohr (130-140°C, 0.65 mm) to obtain 6.51 g (94%) of N.N-diethyl-2- f 1- (trjmethylsilyl) ethyl 1 benzamide .

To a solution of sec-BuLi (0.97M, 5.10 mL, 4.96 mmol) and TMEDA (0.75 mL, 4.96 mmol) in THF at -78°C was added the amide (1.25 g, 4.50 mmol) in THF.

Excess SO2 in THF was added quickly at -78°C then warmed to room temperature. The THF was removed n vacuo and the residue treated at 0°C with two equivalents of a 1:1 solution of sodium hydroxide (0.36 g, 9.0 mmol) and hydroxylamine-O-sulfonic acid (1.0 g, 9.0 mmol) in H2O. The reaction was stirred at room temperature for 4 hrs, extracted with EtOAc, dried over MgS0 , concentrated and flash chromatographed on silica gel with 20% ethyl acetate/hexane to give 0.62 g (41%) of 2-aminosulfonyl-N.N-diethyl-6- Γ1- (trimethylsilyl) -ethyllbenzamide . The benzamide (0.95 g, 2.66 mol) was refluxed in glacial acetic acid (20 mL) for 18 hr, stripped to dryness, triturated with hot cyclohexane (30 mL) and a trace of EtOAc (3 mL) , cooled with scratching and filtered. - 57 - There was obtained 0.81 g (85%) of 4- f 1- (trAmethylSiAyl) -ethy } sa charin, mp 123-125°C.

To the trimethylsilylethylsaccharin (0.25 g, 0.70 mmol) in DMF (9 mL) at room temperature was added H2O (1 mL) and cesium fluoride (0.75g ,4.94 mmol, 7 equivalents) . After 7 hr the reaction was poured into 5% NaOH and extracted with EtOAc. The aqueous layer was acidified with 12N HCl and extracted with Et20-EtOAc (1:1), dried over a2S0 , filtered and stripped to give a colorless solid in quantitative yield. It was recrystallized from 5% Et20-hexanes to give 0.091 g (64%) of 4-ethvlsaccharin. mp 183-185°C.

Preparation 17 The 0.07 g sample of material obtained in the early fractions from the chromatographic separation described above in Preparation 16A consisting predominantly of 2-phenylthiomethyl-4, 7-dimethylsaccharin was reacted with 0.05 ml of sulfuryl chloride in MDC and the product recrystallized from cyclohexane-ethyl acetate to give 20 mg (51%) of 2-chloromethyl-4.7-dimethylsaccharin , mp 107-108°C. - 58 - Preparation 18A To a solution of 40.0 g (0.174 mol) of 2-isopropyl-4-methoxybromobenzene in 600 ml of diethyl ether at 0°C was added 103.68 ml (0.175 mol) of a 1.69 M solution of butyl lithium in diethyl ether. When the addition was complete the solution was cooled to 0°C for one hour and stirred for an additional five hours at ambient temperature, then recooled to -78°C and treated with a solution of 23.68 g (0.175 mol) of N,N-diethyl-carbamyl chloride in 80 ml of diethyl ether. The resulting solution was stirred for about 12 hours while the reaction temperature was allowed to rise and then quenched with saturated ammonium chloride solution. The aqueous and organic layers were separated, the aqueous layer back extracted with ethyl acetate and the combined organic extracts washed once with brine, then dried and the solution taken to dryness to give a crude product which was flash chromatographed on silica gel, eluting with 30% ethyl acetate/hexane to give 34.4 g (79%) of 2=. Asg rop i-4-me hp^ -Nr -dAet]f.ylbensarnAde as an oil which was used as such in the next step without further purification. The oil can be distilled, if desired, and boils at 123-129/0.2-0.3 mm.

Following a procedure similar to that described in Preparation 5 above, the latter (15.0 g, 0.060 mol) in 100 ml of diethyl ether was reacted with 77.8 ml (0.784 mol) of a 1.2M solution of s-butyl lithium in cyclohexane in the presence of 6.98 g (0.06 mol) of tetramethylethylenediamine. The resulting lithium salt was then reacted first with 50 ml of sulfur dioxide and then with 0.181 mol of sodium hydroxylamine-O-sulfonate to give 11. 6 g (59%) of 2-aminosulfonyl-6-isopropvl-4-methoxy-N. N-diethylbenzamide . m.p. 103-105°C (from ethyl acetate/hexane). Eleven grams (0.034 mol) of the benzamide was cyclized in 200 ml of refluxing glacial acetic acid to give 10.3 g of the diethylammo- - 59 - nium salt of 4-isopropyl-6-methoxysaccharin. m.p. 132-135°C.

The latter (0.030 mol), on reaction with 6.14 ml (7.25 g, 0.046 mol) of chloromethyl phenyl sulfide in the presence of 0.98 g (0.003 mol) of TBAB in 250 ml of toluene, afforded 10.1 g (88%) of 2-phenvlthiomethyl-4-isopropvl-6-methoxysaccharin as an oil, 9.7 g (0.026 mol) of which, on reaction with 3.1 ml (5.21 g, 0.039 mol) of sulfuryl chloride in MDC, afforded 6.9 g (88% of 2-chloromethvl-4-isopropvl-6-methoxysaccharin. mp 151-152°C.

Preparation 18B An alternative procedure was also followed: To a solution of 300 mL of Ν,Ν,Ν' ,Ν'-tetra-methylethylenediamine (TMEDA) (1.99 moles) in 4 L of anhydrous ether was added 1550 mL of sec-BuLi (1.3 M) and the system was cooled to -70°C under a nitrogen atmosphere. A solution of 454.2 g of 2-isopropyl-4-methoxy N, -diethylbenzamide (1.82 moles) in 300 mL of anhydrous ether was added dropwise over 30 minutes (the temperature was maintained at or below -60° C during the addition) . After the addition was complete, the reaction was stirred at -70°C for one hour and allowed to warm to -50°C. After holding the temperature at -50°C for 30 minutes, the mixture was cooled back to -70°C.

To this stirred solution was added via cannulating tube a solution of 200 g of SO2 in 200 mL of dry ether precooled to -40°C under positive nitrogen pressure over a 20-minute period. The temperature of the reaction mixture during the addition was maintained below -40°C. (A white powdery precipitate of aryllithium sulphinate separated out almost immediately) . After the addition, the ice-bath was removed and the reaction was allowed to stir at ambient tempera-ture for two hours. It was cooled to -5°C and to this stirred solution was added 190 mL of sulfuryl chloride - 60 - (2.36 moles) dropwise over a 15-minute period maintaining the temperature below 10°C during the addition.

After further stirring for 30 minutes at 0-5°C, a white insoluble precipitate was filtered off and washed with 2 L of anhydrous ether. Removal of the solvent at atmospheric pressure afforded the sulfonyl chloride as a crude dark oil . This crude sulfonyl chloride was dissolved in 1.4 L of THF, cooled to -10°C, and 540 mL of concentrated NH4OH (28%) was added in portions over 15 minutes (the temperature was kept at 15°C or below throughout the addition) . After stirring for 15 minutes at ambient temperature, the THF and excess ammonia were removed under vacuum to give a dark oil, which was diluted with 6.0 L of water and acidified with 3N HCl to pH 1. The light yellow solid was collected by filtration and washed with 800 mL of water. The solid was dried at 60°C under vacuum for 18 hours and recrystal-lized from a mixture of 800 mL of ethyl acetate and 3 L of hexane to give 429 g (72%) of 2-aminosulfonvl-6-isopropyl-4-methoxy-N . N-diethylbenzamid . mp 122-125°C.

A solution of 429.6 g of the diethylbenzamide (1.31 mole) in 1.5 L of acetic acid was refluxed for 20 hours . It was cooled to room temperature and the solvent removed under vacuum. The oily residue was dissolved in 6 L of water and adjusted to pH 1 with 6N HCl. The crude product was collected by filtration and washed with 2 L of water. The solid was dried at 60°C under vacuum for 18 hours and recrystallized from ethyl acetate/hexane to give 303 g (91%) 4-isopropyl-6-methoxysaccharin. mp 188°.

To a suspension of 24 g of paraformaldehyde (0.8 mole) and 86.4 g of chlorotrimethylsilane (1.6 moles) in 200 mL of 1, 2-dichloroethane was added 0.8 ml anhydrous tin (IV) chloride and the resulting solution stirred on a steam bath for one hour. At the end of this period, 51 g of 4-isopropyl-6-methoxysaccharin (0.2 - 61 - mole) was added to the clear solution and the reaction mixture was further refluxed for 18 hours. It was cooled to room temperature, poured into water, the organic layer separated and washed with 50 mL of 2N sodium hydroxide solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under vacuum to give crude product. It was purified by crystallization from ethyl acetate/hexane to give 57 g (87%) of 2-chloromethvl-4-isopropvl-6-methoxvsaccharin. mp 151.

Preparation 19 To a solution of 1.0 g (0.0039 mol) of 4-isopropyl-6-methoxysaccharin in 15 ml of MDC was added at ambient temperature 1.28 g (5.12 ml) of a 1 M solution of boron tribromide in MDC. When addition was complete the reaction mixture was heated under reflux for about five hours, cooled, taken to dryness in vacuo and the residue treated with ice and saturated sodium bicarbonate. The aqueous solution was extracted once with ethyl acetate and then acidified to pH 1 with concentrated hydrochloric acid. Extraction of the mixture with ethyl acetate/diethyl ether (8:2), drying the organic extracts and removal of the solvent in vacuo afforded 0.9 g (96%) of 6-hydrpxy-4^ASoprp ylgflCcharAn as a white crystalline solid which was used as such in the next step.

An alternative procedure was also used. To a stirred suspension of 62.74 g (0.47 mol) of AICI3 in 500 mL of chloroform at 0° was added 43.9 g (0.7 mol) of ethanethiol. Within minutes a clear solution formed. To this a solution of 20.0 g (0.078 mol) of 4-isopropyl-6-methoxysaccharin in 550 mL of chloroform was -added over a 30-min period. This solution was allowed to warm to RT and stirred for 3-4 hr at 60°. After cooling, the mixture was poured into ice-water and acidified with dilute HC1. The solid which separated was collected by - 62 - filtration, washed with water and dried to give 18.4 g (97%) of 6-hvdroxy-4-i sopropvlsaccharin ■ Following a procedure similar to that described in Preparation 4 above, the latter (0.004 mol) was reacted with 0-61 ml (0.0046 mol) of chloromethyl phenyl sulfide in toluene in the presence of 0.133 g (0.004 mol) of TBAB to give 0.32 g (21%) of 4-isopropvl- 6-hvdroxv-2-phenvlthio-methylsaccharin. m.p. 127-129.5, 1.78 g of which was treated with 0.43 ml (0.73 g) of sulfuryl chloride in MDC to give 1.2 g (84%) of 2- 10 chloromethyl-4-isopropyl-6-hvdroxy-saccharin. m.p. 149- 150°C.

Preparation 22, Five grams (0.0207 mol) of 6-hydroxy-4- isopropyl-saccharin was dissolved in 150 ml of methanol J5 and 3.4 g (0.0104 mol) of CS2CO3 was added. The mixture was stirred for 3-4 hr at RT. The excess methanol was removed under reduced pressure and the residue was dried for 2 hr under high vacuum. The residue was then dissolved in 110 mL of DMF and 0.32 g (0.0209 mol) of 20 chloromethyl phenyl sulfide was added. The stirred mixture was heated at 70-75° for 12 hr, cooled, treated with ice water and extracted with 600 mL of 4:1 ethyl acetate: ether. The organic layer was washed with water and saturated NaCl and dried. The solvent was removed 25 under reduced pressure. The residue was purified by flash chromatography with 20% ether in MDC. There was obtained 4.5 g (60%) of 4-isopropyl-6-hvdroxy-2- phenylthio-methvlsaccharin . mp 150-151.5°C which, on reaction with sulfuryl chloride as described in Prepara-30 tion 19, yielded 2-chloromethvl-4-i5opropvl-6- hydroxysaccharin as before.

Preparation 23 To a solution of 5-chloro-2-benzyl-4-isothia- zolin-3-one (J. fie_L. Chem. £, 571 , 1971 ) (9.4 g, 0.04 ,r mol) in MDC (100 mL) was added in one portion 80-85% 3- - 63 - chloroperoxybenzoic acid (10.8 g, 0.06 mol) and the resulting mixture stirred at room temperature overnight under nitrogen. The precipitated solids were filtered off and washed with MDC (50 mL) . The combined filtrate was evaporated to near dryness and the residue partitioned between ethyl acetate (300 mL) and saturated NaHCC>3 (100 mL) . The layers were separated and the organic phase washed with saturated NaHC03 (2 x 100 mL) , brine (1 x 100 mL) and dried. Removal of the solvent in vacuo afforded 10.0 g (99%) of 5-chloro-2-benzyl-4-iso h a^Ol n-3 (2H)-one l-pxjde as a pale yellow oil.

The 1-oxide (10.0 g, 0.04 mol) in glacial acetic acid (200 mL) was treated with 30% H2O2 (100 mL, 0.88 mol) and heated on a steam bath for 2 hr during which time an additional 30 mL (0.26 mol) of 30% H2O2 was added. After heating on a steam bath for an additional hour, the reaction mixture was cooled to room temperature and poured into ice cold water (1L) and stirred. The precipitated solids were collected by filtration, washed with water (2 x 100 mL) , hexanes and air dried to give 4.8 g (45%) of 5-chloro-2-benzvl-4-isothiazolin-3 (2H) -one 1.1-dioxide as a colorless solid.

The dioxide (1.2 g 4.7 mmol) was mixed with 2.02 (11 mmol) of 2-trimethylsiloxy-5-methyl-hexa-l, 3-diene (prepared from 5-methyl-hex-3-ene according to the method of E.J. Corey et al., Tet . 495, 1984) in toluene (50 mL) and refluxed for a period of 20 hr under nitrogen. The resulting mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in THF (25 mL) and treated with 2N HC1 (10 mL) . After stirring under nitrogen at room temperature for 10 min, ether (100 mL) was added and the layers separated. The organic phase was washed with water, brine, dried and evaporated to dryness to give a pale yellow foam. The foam was dissolved in toluene (30 mL) , DBN (1.5 mL) was added and stirred at room tempera-ture - 64 - for 2 nr. MDC (100 mL) and 2N HC1 (50 mL) were added and stirring continued for 5 min. The layers were separated and the organic phase washed with water, brine and dried. Removal of the solvent in vacuo and purification of the residue by flash chromatography on silica gel (5:4:1, hexanes :MDC: ether) gave 0.6 g (39%) of 2=. benzyl-4-isopropyl-6-oxo-tetrahvdro saccharin as a pale yellow foam.

The tetrahydrosaccharin (0.59 g, 1.7 mmol) was dissolved in toluene (50 mL), di ethylamine hydrochlo-ride (1.5 g, 18.0 mmol) and 4 A sieves (2.0 g) were added. The resulting mixture was refluxed with azeotropic removal of water for 96 hr. It was necessary to add additional dimethylamine hydrochloride (0.8 g, 10.0 mmol) and 4 A sieves every 12 hr during this 96 hr period at the end of which time, the reaction mixture was cooled to room temperature and filtered. The filter cake was washed with diethyl ether (100 mL) and the combined filtrates were concentrated in vacuo to give 0.63 g (99% of 2-benzyl-4-isopropyl-6-dimethvlamino- (4.5) dihydrosaccharin as a pale yellow solid.

To a solution of the dihydrosaccharin (0.63 g, 1.7 mmol) in refluxing chloroform (50 mL) was added activated manganese dioxide (4.3 g, 49.5 mmol) in portions over a period of 4 hr. After the addition of the last portion of manganese dioxide, the reaction was refluxed for an additional hr, cooled to room temperature and filtered through a pad of super eel, eluting with ethyl acetate. The combined eluents were concentrated in vacuo and the residue purified by flash chromatography on silica gel (5:4:1, hexanes :MDC: ether) to give 0.32 g (50%) Of 2-benzvl-4-isopropvl-6-dimethy-laminosaccharin as a colorless solid.

The 2-benzylsaccharin (0.32 g, 0.9 mmol) in methanol (20 mL) was treated with ammonium formate (0.24 g, 3.8 mmol) and 10% Pd on Carbon (0.25 g) and refluxed - 65 - for 1 hr, cooled to room temperature and filtered through a pad of super eel, eluting with methanol (100 mli) . The combined eluents were concentrated in vacuo. The residue was dissolved in MDC (10 mL) , glacial acetic acid (0.25 mL) was added, stirred for 5 min. and evaporated to dryness in vacuo to give 0.25 «g (100%) of 4-isopropvl-6-dimethylamino-saccharin as a colorless foam.

Following a procedure similar to that described in Preparation 1, a mixture of 4-isopropyl-6-dimethylamino-saccharin (0.27 g, 1.0 mmol) , chloromethyl phenylsulfide (0.32 g, 2.0 mmol) and tetrabutyl ammonium bromide (0.1 g, 0.2 mmol) in toluene was converted to 0.22 g (56%) of 2-phenylthiomethyl-4-isopropyl-6-dimethylamino-saccharin which was treated with sulfuryl chloride (1.86 mL of 0.31 M solution, 0.6 mmol) to give 0.15 g of a yellow gum that contained 25% (by NMR) of 2-chloromethvl-4-isoproOvl-6-dimethvlamino-7-chloro saccharin.

Preparation 28A Thirty-one grams of 4-isopropyl-l, 2-dimethoxy-benzene was treated with N-bromosuccinimide followed by butyllithium and diethyl carbamyl chloride as in preparation 6B to yield 15.2 g of 2-isopropyl-4, 5-dimethoxy-N,N-diethylbenzamide as a viscous oil. The benzamide was treated according to preparation 18B with butyllithium and sulfur dioxide followed by sulfuryl chloride then ammonia to provide 4.5 g of the sulfonamide, mp 181-182° from ether. This was cyclized in acetic acid as in preparation 18B to obtain 2.86 g of 6.7-dimethoxy-4-isopropvlsaccharin. mp 210-212° from ethyl acetate-hexane .

To a solution of 0.5 g of 4-isopropyl-6, 7-dimethoxysaccharin in 3 mL of DMF was added 0.5 mL of diisopropylethylamine at room temperature. After 15 min, 0.35 g chloromethyl phenyl sulfide was added and the mixture heated at 80° for 16 hrs . The reaction mixture was poured into EtOAc and washed with aqueous Na2C03 solution, aqueous 2N HC1 solution, saturated aqueous NaCl solution. The organic layer was dried over Na2SC> and the solvents removed. Chromatography with MDC gave 0.35 g of desired product, which was used immediately. Treatment of the 0.35 g sample of phenylthiomethyl saccharin in 3 mL of MDC with 0.1 mL of sulfuryl chloride for 30 min at 20° followed by removal of solvents and trituration with hexane gave 0.3 g of Zz. chloromethvl-6.7-dimethoxv-4-isopropvlsacchari .

Preparation 28B To a solution of 5.7 g of methyl piperonylate in 20 mL of dry ether was added 30 mL of 3.0 methyl magnesium bromide in ether at 0° over 20 min. The mixture was stirred for 20 hrs then diluted with 200 mL of ether and washed with water. The organic layer was dried with Na2SC> and the solvents removed to yield 5.6 g of crude 3, -dimethoxy- (1 '-hydroxy-l '-methylethyl) benzene . This material was immediately treated in 50 mL of acetic acid with 1 g of 10% Pd/C under 50 psi of hydrogen for 20 hrs. Filtration to remove catalyst and removal of solvent yielded 4.5 g of S-jsgpropyl-l , 3-ben¾pd;i,px,Ple . The isopropyldioxole was brominated, amidated, sulfonated and cyclized as in 28A to yield 700 mg of 4-isopropyl-6.7-methylenedioxysaccha-rjji, mp 226-228° from ethyl acetate/hexane . Five hundred milligrams of the saccharin was chloromethylated as in 28A to provide 300 mg of 2-chloromethvl-4-isopropyl-6.7-methylenedioxysaccharin. mp 174-176°.

Other 4-R4-R5-saccharins of formula II useful as intermediates for the preparation of the compounds of formula I can be prepared as follows.

Reaction of 2-trifluoromethylbenzoic acid with thionyl chloride affords 2-trifluoromethylbenzoyl chloride, which, on reaction with diethylamine, affords - 67 - 2-trifluoro-methyl-N, -diethylbenzamide . Following a procedure similar to that described in Preparation 5, reaction of the latter with s-butyl lithium and reaction of the resulting lithium salt with sulfur dioxide followed by sodium hydroxylamine-O-sulfonate affords 2-trifluoromethyl-6-aminosulfonyl-N, -diethylbenzamide, which, on heating in glacial acetic acid, affords trifluoro ethylsaccharin .

Similarly, reaction of 2-trichloromethylben-zoic-acid with thionyl chloride affords 2-trichloromethylbenzoyl-chloride, which, on reaction with diethylamine, affords 2-trichloromethyl-N, N-diethylbenzamide. Following a procedure similar to that described in Preparation 5, reaction of the latter with s-butyl lithium and reaction of the resulting lithium salt with sulfur dioxide followed by sodium hydroxyl-amine-O-sulfonate affords 2-trichloromethyl-6-aminosulfonyl-N, N-diethylbenzamide, which, on heating in glacial acetic acid, affords 4-trichloromethylsaccharin .

Reaction of 4-cyclohexylbenzoic acid with thionylchloride affords 4-cyclohexylbenzoyl chloride, which, on reaction with diethylamine, affords 4-cyclohexyl-N,N-diethyl-benzamide. Following a procedure similar to that described in Preparation 5, reaction of the latter with s-butyl lithium and reaction of the resulting lithium salt with sulfur dioxide followed by sodium hydroxylamine-O-sulfonate affords 4-cyclohexyl-2-aminosulfonyl-N, -diethylbenzamide, which, on heating in glacial acetic acid, affords 6-cyclohexvl saccharin.

Reaction of a 2-benzyl-6-aminosaccharin with methanesulfonyl chloride, trifluoromethylsulfonyl chloride or trichloro-methylsulfonyl chloride in MDC in the presence of pyridine followed by transfer hydrogenolysis of the 2-benzyl protecting group, affords, respectively, 6-methyl-sulfonylaminosaccharin. - 68 - 6-trifluoromethylsul (->nvl-aminosaccharin or ^ trichloromethvl-sul fonylaminosaccharin .

Diazotization of 6-aminosaccharin with nitrous acid in an acid medium and decomposition of the resulting diazonium salt in the presence of cupric cyanide or cupric chloride and sulfur dioxide, or cupric chloride and an alkali metal salt of methyl mercaptan or trifluoromethyl mercaptan affords, respectively, £ . cvanosaccharin. 6-ehlorosulfonylsaccharin. £z. methylthiosaccharin or 6-tr.ifluQromet ylth oS¾CChar¾n .

Reaction of the 6-chloro-sulfonylsaccharin situ with ammonia or methanesulfonyl-amide affords, respectively, 6-aminosulfonylsaccharin and 6-methanesuXfon laminQSU,!-fonylsaccharin . Oxidation of 6-methylthiosaccharin and 6-trifluoromethylthiosaccharin with two molar equivalents of 3-chloroperbenzoic acid affords 6-methyl-sulfonvlsaccharin and trifluoromethylsul onylsaccharin. respectively.

Hydrolysis of 6-cyanosaccharin by heating with aqueous sodium hydroxide affords saccharin-6-carboxylic acid . Reaction of 6-cyanosaccharin by heating with a catalytic amount of sulfuric acid in ethanol solution affords ethyl saccharin-6-carboxylate, which, on reduction with lithium borohydride, affords 6-hydroxvmethyl-saccharin. Oxidation of the latter with pyridine : chromium trioxide (2:1) complex (Collins reagent) in MDC affords S-fQrmyJL-saccharin, which, on reductive amination with ammonia and sodium cyanoborohy-dride, affords 6-aminomethvlsaccharin .

Reaction of 4-trifluoromethylbenzoic acid with thionyl chloride affords 4-trifluoromethylbenzoyl chloride, which, on reaction with diethylamine, affords 4-trifluoro-methyl-N,N-diethylbenzam de . Following a procedure similar to that described in Preparation 5, reaction of the latter with s-butyl lithium and reaction of the resulting lithium salt with sulfur dioxide followed by sodium hydroxylamine-O-sulfonate affords 4-trifluoromethyl-2-aminosulfonyl-N, N-diethylbenzamide, which on heating in glacial acetic acid, affords 6-trifluoromethylsacchar n .

Reaction c*f 4-trichloromethylbenzoic acid with thionyl chloride affords 4-trichloromethylbenzoyl chloride, which, on reaction with diethylamine, affords 4-trichloro-methyl-N, N-diethylbenzamide . Following a procedure similar to that described in Preparation 5, reaction of the latter with s-butyl lithium and reaction of the resulting lithium salt with sulfur dioxide followed by sodium hydroxylamine-O-sulfonate affords 4-trichloromethyl-2-aminosulfonyl-N, -diethylbenzamide, which, on heating in glacial acetic acid, affords £ triehloromethvlsaccharin .

Reaction of 2-ethenylbenzoic acid with thionyl chloride affords 2-ethenylbenzoyl chloride, which on reaction with diethylamine, affords 2-ethenyl-N,N-diethylbenzamide . Reaction of the latter with s-butyl lithium and reaction of the resulting lithium salt with sulfur dioxide followed by sodium hydroxylamine-O-sulfonate affords 2-ethenyl-6-aminosulfonyl-N, -diethylbenzamide, which, on heating in glacial acetic acid, affords 4-ethenylsaceharin .

Reaction of 2-ethenyl-6-aminosulfonyl-N, -diethyl-benzamide with bromine affords 2- (1,2-dibromoethyl) - (raminosulfonyl-N, -diethylbenzamide which, on reaction with sodium amide in ammonia affords 2-ethynyl- 6-aminosulfonyl-N, N-diethylbenzamide, which, on heating in glacial acetic acid, affords 4-ethynylsac- Charjn, .

Reaction of ethyl 2-aminobenzoate with two molar equivalents of benzyl chloride in acetone in 'the presence of potassium carbonate affords ethyl 2-(N,N- dibenzylamino) -benzoate which, on saponification in aqueous ethanolic potassium hydroxide and isolation of - 70 - the product from a neutral medium, affords 2-(N,N- dibenzylamino) benzoic acid.

Reaction of the latter with thionyl chloride affords 2- (Ν,Ν-dibenzylamino) enzoyl chloride, which, on 5 reaction with diethylamine, affords 2-(N,N- dibenzylamino)-N,N-diethyl-benzamide. Reaction of the latter with s-butyl lithium and reaction of the resulting lithium salt with sulfur dioxide followed by sodium hydroxylamine-O-sulfonate affords 2-(N,N- 10 dibenzyl) -6-aminosulfonyl-N, N-diethyl-benzamide, which, on heating in glacial acetic acid, affords 4- (N. N- dibenzyl-amino) saccharin which, on catalytic debenzyla- tion with hydrogen over palladium-on-charcoal, affords 4-amino-saccharin . Reductive alkylation of the latter j5 with one molar equivalent of formaldehyde in formic acid affords 4-methvlaminosaccharin .

Reaction of 4-isopropyl-6-hydroxysaccharin (Preparation 19) with Ν,Ν-diethylthiocarbamyl chloride in D F using the procedure described above in Prepara-20 tion 12 affords 4-isoprop l-6- (N, N- diethylthiocarbamyloxy) saccharin which, on heating, rearranges to 4-isopropyl-6- (N, N-diethylcarbamyl- thio) saccharin . The latter, on hydrolysis with alkali, affords 4-isopropvl-6-mercaptosaccharin which . after 25 benzylation, reaction with methyl iodide, and transfer hydrogenolysis affords 4-isopropvl-6-methvlthiosaccha- iJjl. Oxidation of the latter with one or two molar equivalents of 3-chloroperbenzoic acid affords 4- isoproPYl-6-methvl-sulfinvlsaccharin and 4-isopropyl-6- 30 methvlsulfonylsaccharin .

Reaction of 2-isopropyl-4-fluorobenzoic acid with thionyl chloride affords 2-isopropyl-4-fluoroben- zoyl-chloride, which, on reaction with diethylamine, affords 2-isopropyl-4-fluoro-N, -diethylbenzamide . j Reaction of the latter with s-butyl lithium and reaction of the resulting lithium salt with sulfur dioxide followed by sodium hydroxylamine-O-sulfonate affords 2-isopropyl-4-fluoro-6-aminosulfonyl-N, -diethylbenzamide, which, on heating in glacial acetic acid, affords k iso ropy1-6-fluorosaccharin .

Reaction of the latter with thiophenol, 4-methyl-phenylthiophenol, 4-methoxyphenylthiophenol, 4-chlorophenyl-thiophenol, l-mercapto-4-methylnaphthalene or 1-mercaptonaphthalene by heating the reactants in DMF affords, respectively, 4-isopropyl-6-phenylthiosaccha-rin, 4-isopropyl-fi- ( 4-methvlphenvlthio) saccharin. isopropyl-6- (4-methoxvphenyl-thio) saccharin. In ispprgpy3.-g- ( -chiprg- hepy3,thio) -saccharin, i . isopropyl-6- (4-met.hyl-l-naphthvlthiol saccharin and A . isopropyl-6- ( 1-naphthvlthio) saccharin . Oxidation of the latter with one or two molar equivalents of 3-chloroper-benzoic acid affords 4-isopropyl-6-phenylsul inylsac-charin. 4-isopropyl-6-phenvlsulfonvlsaccharin . in isopropyl-6- (4-me hylphenvlsulfinvl) saccharin. An isopropyl-6- (4-methylphenylsulfonvl) saccharin. An isopropyl-6- (4-methoxvphenvlsulfinvl¾ saccharin, Az. 4-jsp-proPvl-6- (4-chlorophenvlsulfinvl) saccharin. 4-Ascp Cp J--6- /4-chlorophenylsulfonvl) saccharin. 4-jsppropy;-6- (4-methyl-l-naphthylsulfinvl) saccharin. ^-jSPpropyA-e- (4-methyl-l-naphthvlsulfonvl ) saccharin . 4-iSPPrPPYJl-6- ( 1~ naphthyl-sulfinvll saccharin and ^-iso rppyl-g- Q-naphthylsulfonvl ) -saccharin .

Reaction of 4-isopropyl-6-hydroxysaccharin (Preparation 19) with one molar equivalent of acetic anhydride, benzoyl chloride or 1-naphthyl carboxylic acid chloride affords, respectively, 4-isopropyl-6-acetoxy-saccharin . 4-jspprppy;.,-6-benzQylpxysacchayin and 4-isopropvl-6- (l-naphthylcarbonyloxy¾ saccharin.

Heating 4-isopropyl-6-fluorosaccharin in DMF with azetidine, pyrrolidine, piperidine, morpholine, 1-benzyl-piperidine, 1-methylpiperazine, imidazole, t- - .72 - butyl alpha-amino-acetate or ammonia affords, respectively, 4-isooroPyl-6- (1-azetidinyl) saccharin . 4-iSOPropvl-6- (1-pvrrol idin l) -saccharin. 4-isopropvl-6- ( l-piperidinyU saccharin. 4- isoproovl-6- f 4-moroholinyl) saccharin, 4-isooropyi-6- (4-benzyl-l-Piperazinvll saccharin. 4-i sooroovl-6- ( 4-methvl-l-pjperazinyl) saccharin. 4-isoprooyl-6- (l-lH-imidazolyl) -saccharin. 4-isooropyl-6- (carbo-t-butoxymethylamino) -saccharin and 4-isopropyl-6-aminosaccharin .

Catalytic debenzylation of 4-isopropyl-6- (4-benzyl-l-piperazinyl) saccharin with hydrogen over palladium on charcoal affords 4-isopropyl-6- (1-pjperazinyl) saccharin. _ Hydrolysis of 4-isopropyl-6- (carbo-t-butoxy-carbonylmethylamino) saccharin with dilute hydrochloric acid and isolation of the product from a neutral medium affords 4-isopropyl-6-carboxvmethvlaminosaccharin .

Reaction of 4-isopropyl-6-aminosaccharin with one molar equivalent of acetyl chloride affords . isopropvl-6-acetylaminosaccharin.

Saponification of 4-carbomethoxysaccharin (Preparation 9D) to the corresponding saccharin-4- carboxylic acid by alkaline hydrolysis, conversion of the acid to the corresponding acid chloride by reaction of the acid with thionyl chloride and reaction of the acid chloride with ammonia affords saccharin-4- carboxamide.

Reaction of each of the 4-R4-R5-saccharins so-prepared with paraformaldehyde and chlorotrimethylsilane in the presence of stannic chloride in ethylene dichloride affords the 4-R4-R5-2-chloro- methylsaccharins of formula IV listed in TABLE B where, in each instance, X is CI.

TABLE B Preparation R4 19A CF3 H 19B CC13 H 19C H 6-cyclohexyl 19D H 6-CH3SO2NH 19E H 6-CF3SO2NH 19F H 6-CCl3S02NH 19G H 6-CN 19H H 6-NH2S02 191 H 6-CH3S02NHS02 19J H 6-CH3S02 19K H 6-CF3S02 19L H 6-HOOC 19M H 6-HOCH2 19N H 6-OHC 19-0 H 6-NH2CH2 19P H 6-CF3 19Q H 6-CCI3 19R CH=CH2 H 19S C≡CH H 19T NH2 H 19U CH3NH H 19V (CH3)2N H 19W CH(CH3)2 6-CH3S 19X CH(CH3)2 6-CH3SO 19Y CH(CH3)2 6-CH3S02 19Z CH(CH3)2 6-F 19AA CH(CH3)2 6-C6H5S 19AB CH(CH3)2 6-(4-CH3C6H4S) 19AC CH(CH3)2 €-(4-CH30C6H4S) 19AD CH(CH3)2 6-(4-ClC6H4S) 19AE CH.(CH3)2 6- (4-CH3~l-naphthyl-S) 19AF CH(CH3)2 6- (1-naphthyl-S) 19AG CH(CH3)2 6-C6H5SO 19AH CH(CH3)2 6-C6H5S02 TABLE B (cont'd) Preparation 19AI CH(CH3)2 6- (4-CH3CgH4SO) 19AJ CH(CH3)2 6-(4-CH3C6H S02) 19AK CH (CH3) 2 6- (4-CH3OC6H SO) 19AL CH(CH3)2 6-(4-CH3OC6H4S02) 19AM CH(CH3)2 6- (4-ClC6H4SO) 19AN CH (CH3) 2 6-(4-ClC6H4S02) 19A0 CH(CH3)2 6- (4-CH3-l-nap thyl-SO) 19AP CH(CH3)2 6- (4-CH3-l-naphthyl-S02) 19AQ CH(CH3)2 6-(l-naphthyl-S0) 19AR CH(CH3)2 6- ( l-naphthyl-S02 ) 19AS CH(CH3)2 6-CH3COO 19AT CH(CH3)2 6-CgH5COO 19AU CH(CH3) 2 6- (1-naphthyl-COO) 19AV CH(CH3)2 6- (1-azetidinyl) 19AW CH (CH3) 2 6- (1-pyrrolidinyl) 19AX CH(CH3)2 6- (1-piperidinyl) 19AY CH(CH3)2 6- (4-morpholinyl) 19AZ CH(CH3) 2 6- (4-benzyl-l-piperazinyl) 19BA CH{CH3)2 6- (4-methyl-l-piperazinyl) 19BB CH(CH3)2 6- (1-lH-imidazolyl) 19BC CH(CH3)2 6- (NHCH2COOC4H9-t) 19BD CH(CH3)2 6-NH2 19BE CH(CH3)2 6- (1-piperazinyl) 19BF CH(CH3)2 6- (NHCH2COOH) 19BG CH(CH3)2 6-(CH3CONH) 19BH CONH2 H - 75 - Preparation 19BI Reaction of isothiazole-5-carboxaldehyde with lithium 3- (triphenylphosphoranylidene)propanoate under standard Wittig conditions provides 4- (5-isothiazolyl) - ; 3-butenoic acid which is reduced and cyclized with aluminum chloride to provide 4-oxo-4, 5, 6, 7-tetrahy- drobenzisothiazole. The 4-oxo compound is reacted with methylenetriphenyl phosphorane under standard Wittig conditions and a methylene is inserted into the 10 resulting 4-methylene compound via a Simmons Smith reaction to provide 6, 7-dihydrospiro [benzisothiazol- . (5H) , 1 '-cyclopropane] which is oxidized with hydrogen peroxide in acetic acid to give 6.7- dihydrospirorbenziso-thiazol-4 (SH) .1 ' -cyclopropane 1.1-,5 dioxide (4-spiro-cyclopropyl tetrahvdrosaccharin) . This is chloromethylated according to the procedure of Preparation 1A to give 2-chloromethyl-4-spirocyclo- propvl-4.5.6.7-tetrahvdrosaccharin .

Preparation 19BJ 20 2-Benzyl-4-isopropyl-6-oxo-tetrahydrosaccharin of preparation 23 is reduced with sodium borohydride and methylated with methyl iodide in the presence of sodium hydride to provide 2-benzyl-4-isopropyl-6-methoxy- tetrahydrosaccharin . This is debenzylated and 2j. chloromethylated as in preparation 23 to provide Z . chloromethvl-4-isopropyl-6-methoxy-4.5.6.7-tetrahy- drosa harin.

Preparation 2QA A mixture of 10.0 g (0.063 mol) of 2,6-20 difluoro-benzoic acid and 66.0 g (0.57 mol) of chlorosulfonic acid was heated at 155-160°C and then poured carefully into 100 ml of ice water. The solids which separated were collected by filtration, air dried and recrystallized from chloroform to give 7.0 g of 2Z. 35 chlorosulfonvl-2.6-difluorobenzoic acid. 0.64 g (0.0025 mol) of which was dissolved in MDC and treated at -10°C - - with a solution of 0.25 g (0.0025 mol) of 1-methyl-piperazine and 0.33 g (0.0026 mol) of diisopropyl-ethylamine. The product which separated was collected by filtration, washed with MDC and dried to give 0.4 g (50%) of 2.6-dif luoro-.l- -methvl-1-pjperazinvl) sulfonvlbenzoic acid.

Preparations 20B - 20G Following a procedure similar to that described in Preparation 20A above, 3-chlorosulfonyl-2. -dichlorobenzoic acid, m.p. 172-175°C (from chloroform) was prepared in 56% yield by heating a mixture of 2, 6-dichlorobenzoic acid with chlorosulfonic acid at 150-160°C.

Reaction of the latter with an appropriate amine (N=B) afforded the 3-aminosulfonyl-2, 6-dichlorobenzoic acids listed in TABLE C below. In each instance products were not further purified but were used as such in the next step.

TABLE C Preparation ϋ≡Β Yi ld 20B 4-morpholinyl 86 20C NHCH2COO-C4H9- (t) 36 4-CH3~l-piperazinyl -CgH5CH2-l-piperazin l N(CH3)CH2CH2N(CH3) 82 NHCH2COOBzl 50 Preparation 21A To a mixture of 1.0 g (0.003 mol) of benzyl 2, 6-dichloro-3-hydroxybenzoate and 0.18 g of a 60% dispersion of sodium hydride in mineral oil in 30 ml of DMF was added a solution of 0.008 mol of 4- (2-chloroethyl) morpholine in 20 ml of t-butyl methyl ether and the mixture heated at 70°C for three hours. The reaction mixture was then taken to dryness and the residue taken up in ethyl acetate and the organic solution washed with water and brine, then dried and concentrated in vacuo to dryness to give 1.25 g (83%) of benzvi 2.6-dichloro-3- \ 2- (4-morpholinvl) ethoxylbenzoate which was dissolved in 1 : 1 ethyl acetate :methanol (50 ml) and reduced with hydrogen over 0.25 g of 10% palladium-on-charcoal . When reduction was complete, the catalyst was removed by filtration, washed with DMF and the combined filtrates taken to dryness in vacuo to give 0.75 g (75%) of 2.6-dichloro-3- Γ2- ( 4-morpholinvl ) ethoxylbenzoic acid.

Preparation 2 3 Following a procedure similar to that described in Preparation 21A, 1.0 g (0.003 mol) of benzyl 2, 6-dichloro-3-hydroxybenzoate was reacted with 0.092 mol of N- (2-chloroethyl) -N, -dimethylamine in 30 ml of DMF and 20 ml of t-butyl methyl ether in the presence of 0.18 g of a 60% mineral oil dispersion of sodium hydride to give a quantitative yield of benzyl 2.6-dichloro-3-i2- fdimethvl-amino) ethoxvl benzoate which was reduced catalytically in a 5:2 solution of ethyl acetate rmethanol over 0.2 g of 10% palladium-on-charcoal. There was thus obtained 0.2 g (22%) of 2.6-dichloro-3- 12- (dimethvlamino) ethoxvlbenzoic acid .

Preparation 21C To a solution of methyl 2, 6-dichloro-4- ethoxybenzoate ( . Qr_s. Chem. 5_0_, 408 1985) (5.5 g, 0.023 mol) in methanol (50 ml.) was added 5N sodium hydroxide (20 mL) . The resulting mixture was heated at reflux for 20 hr, cooled to room tempera ure, concentrated in vacuo and acidified to pi! 1 with 2N I1C.1. The separated solids were collected by filtration to give 5.2 g (100%) of 2.6-dichloro-4-methoxybenzoic acid. which was treated with 60 mL of a 1M solution of boron tribromide (0.06 mol) in dichloroethane (100 mL) at reflux for 2 hr. The resulting mixture was cooled to room temperature and poured onto water/methanol (50 mL of a 9:1 mixture). After stirring for 10 minutes, the mixture was extracted with ether (400 mL) and the organic phase washed with water, brine and dried.

Removal of the solvent in vacuo gave 4.0 g (80%) of 2.6-dichloro-4-hvdroxvbenzoic acid.

The latter (1.05 g, 0.005 mol) was dissolved in 95% ethanol (25 mL) and treated with benzyl chloride (0.71 g, 0.006 mol) and IN NaOH (5 mL) . After refluxing under nitrogen for 2 hr, the reaction mixture was cooled to room temperature and concentrated in vacuo . The residue was acidified with 2N HC1 and extracted with ether. The organic phase was washed with saturated NaiiC03, water and 10% NaOH. After discarding the organic phase, the NaOH washings were acidified with 2M HC1 and reextracted with ether (2 x 50 mL) . The ether extract was then dried and concentrated in vacuo to give 0.63 g (42%) of benzvl-2.6-dichloro-4-hvdroxvbenzoate .

Following a procedure similar to that described in Preparation 21A, 630 mg of benzyl 2,6-dichloro-4-hydroxybenzoate was converted to 350 mg of 2.6-dichloro- 12- (4-moroholinvl¾ ethoxvl benzoic acid .

Pre aration 2 A solution of 1.9 g (0.01 mol) of 2,6-dichloro-3-hydroxybenzaldehyde in 10 mL dry DMF was flushed with nitrogen and 0.3 g of 97% sodium hydride was added with magnetic stirring. Hydrogen was evolved giving a clear red-brown solution. To t is was adder! a solution of 2-dimethy lami nor?I hylchlori (from 2.0 y of / - 79 - the hydrochloride) in 6 mL of t-butylmethyl ether. The solution was heated to reflux for 1/2 hr. Sodium chloride precipitated. The condenser was removed and heating was continued for 1/2 hr. The reaction mixture was concentrated to dryness, taken up in dilute HCl and extracted with methylene chloride. The aqueous layer was basified with 10% a2CC>3 solution, extracted 3X with CH2CI2 and the extracts evaporated to a brown oil which was distilled in a Kugelrohr, bp 155-160°/0.12 mm. The yellow distillate crystallized and was converted to the hydrochloride with ethereal HCl. Recrystallization from CH3CN gave 661 mg of 2.6-dichloro-3- f2-dimethv-laminol ethoxylbenzaldehyde hydrochloride, mp 177-178°.

Freshly prepared silver oxide (from 1.7 g AgN03) was suspended in 1.0 mL of 10% sodium hydroxide solution which was then heated to 55°. The aldehyde (2.62 g, 0.01mm) was added with magnetic stirring. The exothermic reaction raised the temperature to 65° and silver precipitated. Heating was continued at 60° for 1/4 hr. The reaction was filtered and the filtrate extracted 2X with CH2CI2. Evaporation of the CH2CI2 gave 0.804 g of starting aldehyde. The aqueous phase was acidified with 3N HCl and evaporated in vacuo to a white solid which was recrystallized from 10 mL of water.

There was obtained 1.065 g (34%) of 2.6-dichloro-3- Γ2-(dimethvlamino) ethoxyl benzoic acid, mp 234-236°.

Preparations 24B-24D Following a procedure similar to that described in Preparation 24A above, the aldehydes and acids shown in Table D were prepared: - - TABLE D Aldehyde Acid HC1 Salt Preparation N=B ethoxy bp yield mp yield 24B 2-(l-pyrro- 130-140/0.1 mm 41 253-255 10 lidinyl) - ethoxy 24C 2-(l-piper- 160-180/0.1 mm 54 241-242 24 dinyl) ethoxy 24D 2- (diethyl- not distilled — 220-222 15 amino) ethoxy preparation 25 To a solution of chlorine (15.7 g, 0.22 mol) in glacial acetic acid (250 mL) at 0°C was added methyl 3-hydroxybenzoate (15.2g, 0.1 mol). The resulting solution was warmed to room temperature and stirred for 1 hr and evaporated to dryness in vacuo to give 21.4 g of a yellow oil which was found to contain 75% of methyl 2, 6-dichloro-3-hydroxybenzoate by NMR . The oil (21.4 g) was dissolved in acetone (600 mL) , benzyl bromide 19.9 <3r 0.12 mol) and potassium carbonate (22.7 g, 0.16 mol) were added and refluxed under nitrogen for 16 hr. The reaction mixture was cooled to room temperature and the solids filtered off. The filtrate was concentrated in vacuo and the residue taken up in 10% ethyl acetate in hexanes (100 mL) and .chilled in an ice bath. The solids that emerged were collected by filtration and air dried to give 14.3 g (47%) of me hvl 2.6-dichloro-3-benzvloxv-benzpatg .

A solution of methyl 2 , 6-dichloro-3-benzyloxy-benzoate (2.1 g, 6.7 mmol) and 10% aqueous NaOH (25 mL) in methanol (25 mL) was refluxed under nitrogen for 24 hr and cooled room temperature. The resulting mixture was concentrated to one-half the volume in. vacuo and acidified to pH 1 with 2N HC1. the solids that precipitated were collected by filtration, washed with - 81 - water, hexanes and air dried to give 2.0 g (100%) of 2.6-dichloro-3-benzyloxybenzoic acid as a white solid.

Preparation 26 A solution of 5 g of 2, 6-dimethoxy-3-nitroben-zoic acid in THF was hydrogenated in the presence of 10% Pd on C and the resulting amine was acetylated in situ with acetic anhydride and pyridine to provide 0.9 g of 3-acetylamino-2.6-dimethoxybenzoic acid.

Preparation 27 To a suspension of 3.6 g (0.12 mol) of paraformaldehyde in 50 mL of 1, 2-dichloroethane and 30 mL (26 g, 0.24 mol) of trimethylsilyl chloride under nitrogen was added 0.2 mL of stannic chloride and the resulting solution was stirred on a steam bath. After 30 min, 9.55 g (0.05 mol) of 2, 6-dichlorobenzoic acid was added and the reaction heated for an additional 20 hours. Volatiles were removed, the residue dissolved in MDC and washed with NaHC03, dried and stripped to an oil which was triturated in hexane and filtered to obtain 8.5 g of chloromethyl 2.6-dichlorobenzoate . - 82 - Preparation of the Final Products Example I A mixture of 0.5 g (0.0017 mol) of 2-chloromethyl-4, 6-dimethoxysaccharin, 0.33 g (0.0017 mol) of 2, 6-dichloro-benzoic acid and 17 g (0.25 ml, 0.0017 mol) of triethylamine in 15 ml of toluene was heated under reflux for about six hours, then cooled and concentrated to dryness An vacuo. The residue was chromatographed on silica gel, eluting with 40%ethyl acetate/hexane to give 0.44 g (53%) of .6-dimethoxy-2-saccharinylmethyl 2.6-dichlorobenzoate. m.p. 200-201°C.

Following a procedure similar to that described in Example 1A above, the compounds of formula I listed in TABLE 1 below were similarly prepared. The reactions were carried out either in the presence of cesium carbonate, potassium carbonate, triethylamine (TEA), diisopropylethyl-amine (DIPEA) , or 1,8-diazabicyclo- [5.4.0]undec-7-ene (DBU) as basic catalyst or by use of the cesium or thallium salt of the benzoic acid and optionally in the presence of tetra-butylammonium bromide (TBAB) in an appropriate organic solvent as indicated in the column headed "Solv. /Cat" . NMP is N-methylpyrrolidinone . In each of Examples 1D-II, IN, IAI and 1AJ-1AN the products were prepared from the 4-R^-R^-2-bromomethylsaccharin . In all other examples the appropriate 4-R4-R5-2-chloromethylsaccharin was used as the starting material. Here and elsewhere in this specification various heterocyclic or other groups are abbreviated as follows : - 83 - Ac acetyl Mor morpholinyl pip piperazinyl Bzl benzyl azet azetidinyl imidazol imidazolyl pyr pyrrolidinyl pid piperidinyl o υ IMLE_1 (cont'd) Ex R R5 Ar Solv/Cat m.p./Solv Yield 1L CH(CH3)2 9-anthryl toluene 184-185 46 H TEA 1M CH (CH3) 2 2.5-Cl2C6H3 DMF/CH30H 125-126 66 H cs2co3 IN H C6H5 DMF 108-110 21 H Tl salt i-PrOH 1-0 CH3 2.6-Cl2C6H3 DMF 167-168 87 H Tl salt/TBAB IP C2H5 2,6-Cl2CgH3 DMF 113-115 83 H Tl salt/TBAB 1Q CH(CH3)2 2,6-Cl2C6H3 DMF 119-120 83 H Tl salt/TBAB 1 C6H5 2,6-Cl2C6H3 DMF 144-146 80 H Tl salt/TBAB IS H , 6-Cl2-3- (S02-Mor) CgH2 DMF 148-150 38 H Tl salt/TBAB IT H -Cl2-3- (S02NHCH2COOH) CgH2 acetone 205-207 54 H K2C03 1U CH(CH3)2 €-Cl2-3- (S02-4-Moc) CgH2 acetone 139-141 81 H K2C03/TBAB - 86 - H C 4-) CD CQ CO 03 co co CD (0 < < < «C «c < *c < 9 < § u CO 03 03 co 03 ω 03 CO 03 e-< b fc. E→ Cu «» \ • . s O 2 CO X O CO s co 2 o Q O D O Q O * O a CO O s C S - O a O a O O a CO O o CO O CJ a U O O O CJ a O O CM 93 H 2C03/TBAB 1AG CH (CH3)2 2,6-F2-3-.S02-(4-CH3-l-pip) ]CgH2 DMF >161 95 H K C03/TBAB 1AH CHCH3C2H5 2,6-Cl2C6H3 DMF 110-113 26 H K2C03/TBAB 1AI H 2,6-Cl2C6H3 DMF 158-159 31 H Tl salt i-PrOH 1AJ H 2,6-F2C6H3 EtOH 126-127 28 H Tl salt i-PrOH 1AK H 2,6-(CH3)2C6H3 EtOH 138-140 29 H Tl salt i-PrOH 1AL H 2,3,6-Cl3CgH2 EtOH 174-176 33 H Tl salt i-PrOH 1AM H 9-anthryl xylene 208-210 52 H TEA CH3CN IAN H 2,6-(CF3)2C6H3 DMF 153-155 49 H Tl salt 1A0 CH(CH3)2 2,4-Cl2C6H3 DMF 130-131.5 62 H K2C03/TBAB σ x X < t ε-1 S < < > < < TABLE 1 (cont'd) Ex R4/R5 Ar Solv/Cat m.p./Solv Yield C2H5 2,6-Cl2-C6H3 D F 193-195 71 5,7-(CH30)2 K2C03/TBAB iPrOH CH(CH3)2 2,6-Cl2-C6H3 DMF 183-185 6- (4-CH3-l-pip) K2C03 EtOH/Bt20 n-C3H7 2, 6-Cl -CgH3 DMF 138-140 79 5,6-(CH30)2 K2C03 iPrOH/hex CH(CH3)2 2,6-Cl2-C6H3 DMF 171-173 75 5,6- νο - 91 - C fc- ca 3 rn a > CQ ca CQ ca lABLE-L (cont'd) (a) 2-Chloromethylsaccharin reacted with 2, 6-dichloro-3-carbo-t-butoxycarbonyl-methyl- aminosulfonylbenzoic acid and the product hydrolyzed with trifluoroacetic acid in MDC to give the corresponding 2-saccha r inylmethyl ca boxymethyl-amino- sulfonylbenzoate in 76% yield. (b) HC1 salt. (c) 2-Chloromethyl-4-isopropylsacchar in reacted with 2, 6-dichloro-3-benzyloxy- carbonylmethylatninosulfonylbenzoic acid and the product catalytically debenzylated under 1 atm. of hydrogen over palladium/charcoal in EtOAc with 17% acetic acid to give the corresponding acid in 80% yield. (d) 2-Chloromethyl-4-isopropylsaccharin reacted with 2 , 6-dichloro-3-benzyloxybenzoic acid, and two products were obtained, one in which the benzoic acid moiety had been dechlorinated. (e) HCl.5/2 H20. (f) HCl.3/2 H20. (g) CH3S03H salt. - 93 - Example 1AW The cesium salt of 2 , 6-dichlorobenzoic acid was prepared from 4.48 g (0.0235 mol) of 2, 6-dichlorobenzoic acid and 3.82 g (0.0117 mol) of CSCO3 in methanol. The salt was isolated by removing the solvent under reduced pressure and drying under high vacuum for 1/2 hr. The dried salt was suspended by stirring in 10-15 mL of DMF and 3.4 g (0.0117 mol) of 2-chloromethyl-6-hydroxy-4-isopropylsaccharin was added. The mixture was heated at 80° for 2-3 hr, cooled, diluted with water and extracted with 200 mL of 7:3 ether: ethyl acetate. The organic layer was washed with water and saturated NaCl and dried. The solvent was removed and the residue was purified by flash chromatography with ethyl acetate-hexane on silica gel to give 4.53 (87%) of 6-hvdrr>xy-4-isopropyl-2-saccharinylmethyl 2.6-dichlorobenzoate (no mp) .

Example 2A A solution of 1.4 g (0.0026 mol) of 4-isopropyl-2-saccharinylmethyl 2, 6-dichloro-3-benzyloxybenzoate in 50 ml of ethyl acetate was treated with 0.3 g of 10% palladium-on-charcoal and 0.5 ml of acetic acid and the mixture stirred under 1 atm. of hydrogen for sixteen hours. The catalyst was removed by filtration, and the filtrate was taken to dryness jn vacuo to give 1.16 g (100%) of 4-isopropyl-2-saccharinylmethvl 2.6-dichloro-3-hydroxvbenzoate. m.p. 78-80°C.

Example 2B Following a procedure similar to that described in Example 2A above, 1.2 g (0.0018 mol) of 4-isopropyl-2-saccharinylmethyl 2, 6-dichloro-3- (4-benzyl-l-piperazinyl-sulfonyl)benzoate (Example 1Z) was reduced with hydrogen in 50 ml of ethyl acetate and 2 ml of acetic acid over 0.3 g of 10% palladium-on-charcoal and the product converted to the hydrochloride salt to give - 94 - 0.5 g (68%) of 4-isopropYl-2-saccharinylmPthvl 2.6-dichloro-3- (1-pjperazi nylsulfonvl ) benzoate hvdrochloridP. m.p. above 171°C.

Exa e 2C A mixture of 4-isopropyl-6-methoxy-2-saccharinylmethyl-2, 6-dichloro-3-benzyloxybenzoate of Example 1BU (2.5 g, 4.4 mmol) , 10% Pd on Carbon (0.7g) and glacial acetic acid (1 mL in ethyl acetate (100 mL) was stirred under 50 psi hydrogen in a Parr hydrogenator for 1.5 hr. The resulting mixture was filtered through a pad of super eel eluting with ethyl acetate (100 mL) . The combined filtrate was washed with saturated NaHCC>3, water, brine and dried. Removal of the solvent in vacuo and crystallization from 1:1 ether/hexanes gave 2.1 g (100%) of 4-isopropyl-6-methoxv-2-saccharinYlmethyl 2.6-dichloro-3-hydroxybenzoate . mp 152-154°.

Exa le 2P By a process analogous to that of Example 2A, 0.41 g of 4-isopropyl-6-methoxy-2-saccharinylmethyl 2,6-dichloro-3-benzyloxycarbonylmethylaminosulfonylbenzoate of Example 1BV was catalytically debenzylated under 1 atm. of hydrogen over palladium/charcoal in ethyl acetate with 20% acetic acid to give 0.16 g (45%) A . isopropyl-6-methoxv-2-saccharinvlmethvl 2.6-dichloro-3-carboxvmethylamino-Bulfonvlbenzoate. mp 204-206°.

Example 3A A solution of 1.05 g (0.0024 mol) of 4-isopropyl-2-saccharinylmethyl 2, 6-dichloro-3-hydroxybenzoate (Example 2A), 0.50 g (0.0026 mol) of t-butyl alpha-bromoacetate and 0.48 g (0.0035 mol) of potassium carbonate in 25 ml of acetone was heated under reflux for seven hours, then cooled to ambient temperature, filtered and the filtrate taken to dryness to give 0.32 g (24%) of 4-isopropvl-2-saccharinvlmfil-hvI 2, 6-dich3,pro-3-t-buto^ycarbonylmethoxybenzoate, which was dissolved in 10 ml of MDC containing 2 ml of - 95 - trifluoroacetic acid. The solution was stirred at ambient temperature under nitrogen for two hours, taken to dryness and the residue triturated with hexane/ether. The resulting solid was collected by filtration to give 0.18 g (64%) of 4-isopropyl-2-saccharinylmethvl 2.6-dichloro-3-carboxvmet.hoxyhsnzoate. m.p. 210-212°C.

E ample 3B A solution of 0.78 g (1.6 mmol) of 4-isopropyl-6-methoxy-2-saccharinylmethyl-2, 6-dichloro-3-hydroxybenzoate, 0.38 g (2.0 mmol) of t-butyl a-bromoacetate and 0.3 g (2.1 mmol) of potassium carbonate in 50 mL acetone was heated under reflux for 16 h, then cooled to room temperature, filtered and the filtrate taken to dryness. Purification of the residue by flash chromatography on silica gel (4:2 hexanes :ethyl acetate) gave 0.65 g (67%) of 4-isopropvl-6-methoxv-2-san harinvlmethyl 2.6-dichloro-3-t-butoxycarbonvl-methoxybenzoate. The t-butyl ester (0.55 g, 0.9 mmol) was dissolved in 15 mL MDC containing 5 mL of trifluoroacetic acid. The solution was stirred at room temperature under nitrogen for 2 hr, taken to dryness and the residue triturated with hexane/ether. The resulting solid was collected by filtration to give 0.4 (82%) of 4-isopropvl-6-methoxv-2-saccharinylmethvl 2.6-dichloro-3-carboxvmethoxvbenzoate. mp 206-208°.

Example 4 By reaction of an appropriate 4-R^-R^-2-halomethylsaccharin of formula IV with an appropriate arylcarboxylxc acid using the procedure described above in Example 1A, or by reaction of the appropriate saccharin of formula II with the appropriate chloromethyl benzoate using the procedure described in Example 11 below, the compounds of formula I listed in TABLE 2 below can be prepared. - 96 - 1A£LE_2. (cont'd) Example R R 4U CC13 H 2,6-Cl2C6H3 4V H 6-cyclohexyl 2,6-Cl2C6H3 4W H 6-CH3S02NH 2,6-Cl2C6H3 4X H 6-CF3S02NH 2,6-Cl2C6H3 4Y H 6-CCl3S02NH 2,6-Cl2C6H3 4Z H 6-CN 2r6-Cl2C6H3 4AA H 6- H2S02 2,6-Cl2C6H3 AB H 6-CH3S02NHS02 2,6-Cl2C6H3 4AC H 6-CH3S02 2,6-Cl2C6H3 4AD H 6-CF3S02 2,6-Cl2C6H3 AE H 6-HOOC 2,6-Cl2C6H3 4AF H 6-HOCH2 2'6-C12C6H3 4AG H 6-OHC 2,6-Cl2C6H3 4AH H 6- H2CH2 2,6-Cl2C6H3 4AI H 6-CF3 3- (l-azet)CgH4 AJ H 6-CCl3 f 6~Cl2CgH 4AK CH=CH2 H 2,6-Cl2C6H3 AL C≡CH H 2, 6-Cl2C6H3 4AM H2 H 2,6-Cl2C6H3 4AN CH3NH H 1-d-imidazoDCgH ABLE 2 (cont'd) Example R ≥i 4AO (CH3)2N H 2 6—Cl2CgH3 AP CH(CH3)2 6-CH3S 2r6-Cl2CgH3 AQ CH(CH3)2 6-CH3SO 2, 6-Cl2CgH3 4AR CH(CH3)2 6-CH3S02 2 6—Cl2CgH3 4AS CH(CH3)2 6-F 3-(l-pyr.)CgH CH(C 2,6-Cl2CgH3 4AT H3)2 6 5 4AU CH(CH3)2 6-( -CH3C6H4S) 2 6—Cl2CgH3 4AV CH(CH3)2 6-(4-CH3OCgH4S) 2,6-Cl2CgH3 4AW CH(CH3)2 6-(4-ClC6H4S) 2 f 6—Cl2CgH3 4AX CH(CH3)2 6-(4-ClC6H4S) 2,6-Cl2CgH3 4AY CH(CH3)2 6-(l-naphthyl-S) 2 6-Cl2CgH3 4AZ CH(CH3)2 6-C6H5SO 2,6-Cl2C6H3 4BA CH(CH3)2 6-C6H5S02 2'6-C12C6H3 4BB CH(CH3)2 6-(4-CH3C6H4SO) 2,6-Cl2CgH3 4BC CH(CH3)2 6-(4-CH3C6H4S02) 2,6-Cl2CgH3 4BD CH(CH3)2 6-(4-CH3OC6H4SO) 2 6-Cl2CgH3 4BE CH(CH3)2 6-(4-CH3OCgH4S02) 2,6-Cl2C6H3 BF CH(CH3)2 6- (4-ClCgH4SO) 2,6-Cl2CgH3 4BG CH(CH3)2 6-(4-ClC6H4S02) 2 , 6-Cl2CgH3 4BH CH(CH3)2 6- (4-CH3-1-naphthyl-SO) 2,6-Cl2CgH3 IAJBLEL2 (cont'd) Example R4 R Ar 4BI CH(CH3)2 6- (4-CH3-l-naphthyl-S02) 2,6-Cl2C6H3 4BJ CH(CH3)2 6- ( 1-naphth 1-SO) 2,6-Cl2C6H3 4BK CH(CH3)2 6- ( l-naphthyl-S02 ) 2,6-Cl2C6H3 4BL CH(CH3)2 6-CH3COO 2,6-Cl2C6H3 4BM CH(CH3)2 6-C.-H.-COO 2,6-Cl2C6H3 6 5 BN CH(CH3)2 6- ( 1-naphthyl-COO) 2,6-Cl2C6H3 4BO CH(CH3)2 6- ( 1-azetidinyl ) 2,6-Cl2C6H3 4BP CH(CH3)2 6- (l-pyrrolidinyl) 2,6-Cl2C6H3 4BQ CH(CH3)2 6- (1-piperidinyl) 2,6-Cl2C6H3 4BR CH(CH3)2 6- (4-morpholinyl) 2 6-Cl2C6H3 4BS CH(CH3)2 6- (4-benzyl-l-piperazinyl) 2,6-Cl2C6H3 4BT CH(CH3)2 6- (4-methyl-l-piperazinyl) 2,6-Cl2C6H3 4BU CH(CH3)2 6- (1-lH-imidazolyl) 2,6-Cl2C6H3 4BV CH(CH3)2 6- (NHCH2COOC4H9-t) 2,6-Cl2C6H3 BW CH(CH3)2 6-NH2 2,6-Cl2C6H3 4BX CH(CH3)2 6- (1-piperazinyl) 2,6-Cl2C6H3 4BY CH(CH3)2 6-(NHCH2COOH) 2 6-Cl2C6H3 4BZ CH(CH3)2 6-(CH3CONH) 2,6-Cl2C6H3 CA CONH2 H 2,6-Cl2C6H3 - 100 - Example 4CB According to the procedure of Example 4, 2-chloromethyl-4-spirocyclopropyl- ,5,6,7-tetrahydrosaccharin of preparation 19BI is coupled with 2, 6-dimethylbenzoic acid to provide 4-spirocyclopropyl- 4r 5r 6t7-te rah dro-¾-sflccharin ltneth l 2r 6-dime hvlbenzoate .

Example 4.CC According to the procedure of Example 4, 2-chloromethyl-4-isopropyl-6-methoxy-4, 5, 6, 7-tetrahydrosaccharin of preparation 19BJ is coupled with 2, 6-dimethylbenzoic acid to provide 4-isopropyl-6-methoxv-4.5.6.7-tetrahydro-2-saccharinvlmethvl 2.6-d me hyl ¾nzoa e · Example 5A To a solution of 500 mg (1.1 mmol) of 6-hydroxy-4-isopropyl-2-saccharinylmethyl 2, 6-dichlorobenzoate in 10-15 ml of THF were added 298 mg (1.14 mmol) of triphenylphosphine, 52 mg (1.13 mmol) of ethanol and 198 mg (1.1 mmol) of diethyl azodicarboxylate at RT. The mixture was stirred for 1 1/2 hr and then chromatographed on silica gel with 10% ethyl acetate in hexane to yield 370 mg (70%) of £z. ethoxv-4-j sopropvl-2-saccharinvlmethvl 2.6-dichlorobenzoate as a white powder, mp 140-141°C.

Following the procedure of Example 5A, the compounds of Table 3 were prepared from the 6-hydroxy compound of Example 1AW. - 101 - Table 3 Example R5 vo (%) 5D 6- (OCH2CH2) 2OCH3 119-120 74 5E 6-OCH2COOCH3 foam 64 5F 6-OCH2CH(OCH3)CH2OCH3 gum 53 5G 6-O-cyclobutyl 150-151 44 The protected glycerol used in the synthesis of Example 5F was obtained as follows: A solution of 10.0 g (0.055 mol) of DL^ot-O-benzylglycerol in a little THF was added to a suspension of 15.38 g (0.137 mol) of potassium tert-butoxide in 300 mL of THF. The mixture was stirred for 1 hr at RT and 18.72 (0.132 mol) of iodomethane was added. A white solid immediately separated. The reaction was stirred for 10 hr at RT, cooled, carefully diluted with sodium chloride solution and extracted with ether. The organic layer was washed with water, 5% HC1, water and saturated NaCl and dried. The solvent was removed and the residue was purified by flash chromatography to give I . benzyloxv-2 , 3-dime hoxvoropane . 9.16 g (79%), as an oil.

A solution of 8.8 g (0.042 mol) of this material in 200 ml of MeOH was hydrogenated using 1.1 g of 10% Pd/C at 50 psi. The catalyst was removed by filtration and the solvent under reduced pressure to give 4.4 g (87%) of 2.3-dimethoxv-l-prooanol .

Example 51 6-Ethoxy-4-isopropyl-2-phenylthiomethylsaccharin was prepared from the 6-hydroxy analog (Preparation 19) by the procedure of - 102 - Example 5A in 85% yield as a solid, mp 111.5-112.5°C, which was converted to 2-chlorome1:hyl-6-ethoxy-4-isopropvlsaccharin in 91% yield, mp 127-128°C, following the procedure of Preparation 18A.

Example 5J To a solution of 4-isopropyl-6-hydroxysaccharinylmethyl 2, 6-dichlorobenzoate of Example 1C (0.44 g, l.O mmol) in MDC (20 mL) was added at 0°C triethylamine (0.3 g, 3.0 mmol) and trifluoromethanesulfonic anhydride (0.37 g, 1,3 mmol). After being stirred at 0°C for 10 min, the reaction mixture was diluted with MDC (50 mL) and washed with saturated NaHC03, brine and dried. Removal of the solvent in vacuo and purification of the residue by chromatography on silica gel (5% ethyl acetate in MDC) gave 0.53 g (88%) of 4-jspprQpyl-6-tri luoromethanesulfonvloxvsaccharinvlmethvl 2.6-dichlorobenzoate as a colorless foam.

The trifluoromethanesulfonate (0.28 g, 0.49 mmol) was mixed with l-methyl-2-trimethylstannyl-pyrrole (0.19 g, 0.78 mmol), tetrakis (triphenylphosphine) palladium (0) (0.012 g, 0.01 mmol), lithium chloride (0.062 g, 1.5 mmol) and 2, 6-di-tert-butyl-4-methyl-phenol (O.Olg, 0.05 mmol) in p-dioxane (10 mL) and refluxed under nitrogen for 30 min. The resulting dark reaction mixture was cooled to room temperature, diluted with ether (50 mL) and filtered through a pad of super cel. The filtrate was washed with water, brine and dried. Removal of the solvent i vacuo and purification of the residue by flash chromatography on silica gel (7:2:1, hexanes:MDC: ether) gave 0.22 g (92%) of 4-isopropyl-6-r2-il-methvlTpvrrolidinvl1saccharinvlmethvl 2.6-dichlorobenzoate as a pale yellow solid, mp 125-127°. - 103 - Example 5K 4-Isopropyl-6-trifluoromethanesulfonyloxy-saccharinylmethyl 2, 6-dichlorobenzoate, prepared as in Example 5J, (0.7 g, 1.2 mmol) in THF (10 mL) was cooled to ~5°C and was treated with 40% aqueous dimethylamine (0.6 mL, 5.3 mmol) and stirred at room temperature overnight. The resulting mixture was diluted with saturated NaHC03 solution (20 mL) and MDC (250 mL) . The layers were separated and the organic phase washed with water, brine and dried. Removal of the solvent ia vacuo and purification of the residue by chromatography on silica gel (6:3:1, hexanes : MDC :ether) gave 0.2 g (35%) Of 4-isopropyl-6-dimethvlaminosaccharinvlmethvl 2.6-dichlorobenzoate. mp 177-179°.

Exam le 5L A solution of 42 mg of 4-isopropyl-6-hydroxy-saccharinylmethyl 2, 6-dichlorobenzoate of Example 1C, di- (see-butoxymethyl) methylamine and toluene was heated at 80° for 1 hour, cooled and volatiles removed.

Slurrying in hexane yielded 30 mg of 2- (2.6-dichlorobenzoyloxymethyl ) -8-methy1-2.3.7.8-tetrahvdro- 9H- Γ1.31 oxazino Γ 6.5-σΊ benziso-thiazol-3-one 1 , 1-dioxide .

Example 6 A solution of 600 mg (1.1 mmol) of the isopropylidene of Example 5C, Table 3, and 176 mg (0.9 mmol) of p_-toluenesulfonic acid monohydrate in methanol-chloroform was stirred overnight . The mixture was chro atographed on silica gel to give 290 mg (53%) of 6-(2 r 3-d; ydrpxypropp;xy) - -isoprppylsa^ch^rjn.ylmethyl 2 , 6~ tiichlorobensQate as a foam.

Example 7 To a solution of 1.0 g (2.3 mmol) of 6-hydroxy-4-isopropyl-2-saccharinylmethyl 2, 6-dichlorobenzoate in 40 ml of acetone at RT were added 0.62 g (4.5 mmol) of anhydrous K2CO3 and 0.66 g (93.4 - 104 - mmol) of jL-butyl bromoacetate . The mixture was stirred for 4-5 hr and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography to give 1.13 g (90%) of 6- (2-t-butoxy-2-oxof>thoxY)-4-isopropyl-2-saccharinvlmethvl 2.6-dichlorobenzoate as a glass.

Example 7p In a similar manner 6- f2-benzvloxy-2-oxoethoxy)-4-isopropvl-2-saccharinvlmethvl 2.6-dichlorobenzoate was obtained as a glass in 61% yield from the 6-hydroxy compound and benzyl bromoacetate.

Example 8 To freshly distilled cyclopentadiene (25 mL) at 0°C was added 4-bromo-2- (tert-butyl) isothiaziol- 3(2H)-one 1, 1-dioxide (Helv. Chim. Acts.., 2Z, 1416, 1989) (7.9 g, 0.03 mol) . After stirring at 0°C under nitrogen for 16 hr, the reaction mixture was concentrated in vacuo . The residue was purified by filtering through silica gel, eluting with hexanes (500 mL) followed by 20% ethyl acetate in hexanes (500 mL) . The latter eluents were concentrated in vacuo to give 9.8 g (100% of the norbornene adduct, 3a-bromo-2-t-butvl-3a . .7.7a-tetrahvdro- .7-methano-l .2-benzisothiazol-3(2H)-one 1.1-dioxide. as a white solid.

The adduct (0.4 g, 1.2 mmol) in 25 mL of ethyl acetate containing 5% Pd on CaC03 (0.2 g) was stirred under one atmosphere of hydrogen for 4 hr, and the reaction mixture was filtered through a pad of silica gel, eluting with ethyl acetate (100 mL) . The eluents were concentrated in. vacuo and the residue crystallized from hexanes to give 0.4% (100%) of the bromo norbornane as a white crystalline solid.

To a solution of the bromo norbornane (3.7 g, 0.011 mol) in toluene (25 mL) at 0°C was added diazabicyclo-nonene (1.37 g, 0,011 mol) in toluene (10 mL) . After stirring at 0°C for 20 min, silica gel (25 - 105 - g) was added to the reaction mixture. The resulting slurry was loaded on top of a 15 cm pad of silica gel and eluted with 20% ethyl acetate in hexanes (800 mL) . The eluents were concentrated in vacuo to give 2.8 (100%) of the dehydrobrominated compound as a white solid.

The 2-t-butyl-4/ 5, 6, 7-tetrahydro-4, 7-methano-l,2-benzisothiazol-3 (2H) one 1,1-dioxide (2.8 g, 0.011 mol) in trifluoroacetic acid (30 mL) was heated at reflux for 48 hr and let stand at room temperature for 4 days. The resulting mixture was concentrated in. vacuo, treated with methanol (20 mL) and evaporated to dryness. The residue was taken up in ether (100 mL) and washed with saturated NaHC03 (1 x 50 mL) . The layers were separated, the aqueous phase acidified to pH 1 with 2N HC1 and extracted with MDC (2 x 100 mL) . The combined organic extracts were dried and concentrated in vacuo to give 0.9 g (42%) of the bicyclo (2.2.1) saccharin derivative as a white solid.

A mixture of the bicyclo (2,2,1) saccharin derivative (0.9 g, 5 mmol), chloromethyl phenylsulfide (0.07 g, 7 mmol) and tetrabutylammonium bromide (0.36 g, 0.16 mmol) in toluene (50 mL) was refluxed under nitrogen for 16 hr, cooled to room temperature and evaporated to dryness under vacuum. The residue was purified by flash chromatography on silica gel (100 g) using 100% MDC as the eluent to give 1.05 (72%) of the sulfide as a viscous oil.

The sulfide (1.05 g, 3 mmol) in dichloromethane (100 mL) was treated with sulfuryl chloride (0.66 g, 5 mmol) and stirred for 2 hr. The resulting yellow solution was diluted with MDC (100 mL) , washed with saturated NaHCC>3 solution , dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (33% MDC in hexanes) to give 0.66 g (81%) of 2-chloromethvl-4.5.6.7- - 106 - tetrahvdro-4.7-methano-l .2-hpnzisothiazol-3 (2H) -one .1-tiioxide · The 2-chloromethyl compound (0.66 g, 2.7 mmol) was treated with 2, 6-dichlorobenzoic acid (0.56 g, 2.9 mmol), anhydrous potassium carbonate (0.55 g, 4.0 mmol) and tetrabutylammonium bromide (0.2 g, 0.6 mmol) in DMF (2.5 mL) at 70°C for 1 hr. The resulting mixture was concentrated ±∑\ vacuo, diluted with ethyl acetate (100 mL) and filtered. The filtrate was washed with water, saturated NaHC03, water and brine. The organic phase was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (3:6:1, MDC:hexanes: ether) to give 0.5g (47%) of 2- 12.6-dichlorobenzoyloxymethyl) 4.5.6.7-tetrahvdro-4.7-methano-1.2-benzisothiazol- (2H)-one 1.1-dioxide as a colorless foam.

Examples 8B and 8C By a process analagous to that of Example 8A, it is contemplated that cyclohexadiene and 1, 1-dimethyl-cyclopentadiene may be converted respectively to 4.5.6.7-tetrahvdro- .7-ethano-l .2-benzisothiazol-3 (2H) -one 1.1-dioxide and 8.8-dimethvl-4.5.6 .7-tetrahvdro-4,7-methano-1.2-benzisothiazol-3 2H) -one .1-dioxide .

Examples 9A-9D General procedure for the preparation of methvl-2-alkylcvclohexan-6-one carboxvlate : To a suspension of anhydrous Cul (10 mmol) in anhydrous THF (100 mL) was added Me2S (100 mmol) and the resulting solution was cooled to -78°C. The Grignard reagent (20 mmol) was added over a period of 15 min. After being stirred at -78°C for an hour, a solution of cyclohexenone (10 mmol) in THF was added and stirring continued for another 15 min. To the resulting mixture was added HMPA (5 mL) and, after 15 min, methyl cyanoformate (30 mmol) in THF (20. mL) and - 107 - the reaction warmed to room temperature and stirred overnight. The reaction mixture was quenched with 2N HC1 (50 mL) . The layers were separated and the aqueous phase extracted with Et20 (1 x 100 mL) . The combined organic extracts were washed with saturated NH4CI solution (3 x 50 mL) , water (2 x 50 mL) , brine (1 x 50 mL) and dried (Na2≤0 ) . Removal of the solvent in vacuo and purification by either Kugelrohr distillation or flash chromatography afforded the desired methyl 2-alkylcyclohexan-6-one carboxvlate (Table E) .

Ta le E Intermediate Alkyl Yield b.p.

B Me 82 C Et 70 100-110°C (0.2 mm) iPr 74 106-109°C (0.5 mm) General procedure for the preparation of methvl 2-benzylthio-6-alkylcyclohex-2-ene carboxylate and 2-benzvlthio-6-alkvlcvclohex-l-ene carboxvlate : A mixture of methyl-2-alkylcyclohexan-6-one carboxylate (1 eq) , benzylmercaptan (1.1 eq) and the acidic clay montmoril-lonite, KSF (1,5 times the weight of methyl-2-alkylcyclohexan-6-one carboxylate) in anhydrous toluene (50-100 mL) was refluxed under nitrogen with azeotropic removal of water for 12-14 hr and cooled to room temperature. The solids were filtered off and washed with ether. The combined filtrate was washed with 10% a2C03, water, brine and dried. Removal of the solvent in vacuo and purification of the residue by flash chromatography on silica gel (10% ether in hexanes) gave a mixture of methyl 2-benzylthio-6-alkylcyclohex-2-ene carboxvlate and 2-benzylthio-6-a3 kylcyclohex-l-ene carboxylate (Table F) which was used in the next step as a mixture. - 108 - Table F Intermediate Alkyl Combined Yield of Mixture A H 40 B Me 44 C Et 50 D iPr 52 General procedure for he preparation of 4-alkvl-r.errahyriro saccharins; A solution of methyl 2-benzylthio-6-alkylcyclohex-2-ene-carboxylate and 2-benzylthio-6-alkylcyclohex-l-ene carboxylate (1-10 mmol of the mixture) in 10 mL of MDC was diluted with 20-50 mL of glacial acetic acid and 1-5 mL of water, the mixture cooled to -10°C, and chlorine gas was bubbled through the mixture until the exothermic reaction subsided. The mixture was then stirred for 10 minutes and taken to dryness to give a mixture of methyl 2-chlorosulfonyl-6-alkylcyclohex-2-ene carboxylate and 2-chlorosulfonyl-6-alkylcyclohex-l-ene carboxylate, which was dissolved in 10 mL of THF and added to 25 mL of a solution of concentrated ammonium hydroxide while cooling in an ice/acetone bath. After stirring for 2 hr, the reaction mixture was concentrated in vacuo, the residue taken up in water, acidified to pH 1 with 2N HC1, and extracted with MDC. The organic phase was dried and concentrated in vacuo to give a mixture of methyl 2-aminosulfonyl-6-alkylcyclohex-2-ene carboxylate and 2-aminosulfonyl-6-alkylcyclohex-l-ene carboxylate.

The mixture was dissolved in methanol and added to a freshly prepared solution of sodium methoxide (10-50 mmol) and stirred at ambient temperature for 12 hr.

The reaction mixture was concentrated in vacuo, diluted with water and extracted with ether. The organic phase was discarded, and the aqueous phase was acidified to pH 1 with concentrated HC1 and extracted with MDC. The organic extracts, on washing with brine, drying and - 109 evaporation to dryness, afforded 4-alky3-4.5.6.7-tetrahvdrobenzisothiazol-3-one 1.1-dioxide or 4-a.3,k,yI-tetrahydro saccharins (Table G) .

Table g Intermediates Alkyl Yield A H 50 B Me 85 C Et 80 D iPr 74 A mixture of 4-alkyl-4, 5, 6, 7-tetrahydrobenzisothiazol-3-one 1, 1-dioxide (4-alkyltetrahydro saccharin) (1.0 eq) , chloromethyl phenyl sulfide (1.5 eq) and tetrabutylammonium bromide (0.2 eq) in toluene (25 L/g of saccharin) was refluxed under nitrogen for 16-24 hr and then cooled to room temperature. The resulting mixture was evaporated to dryness and the residue chromatographed on silica gel eluting with hexanes/MDC (1:1 to 1:3) to give the corresponding 2=. phftnylt.hlfniM*thyl~4-alkyl-4.5.6.7-tft rahydrnhftngisothia ole -3-one 1.1 dioxide or 2=. phenylthjomg hyl-4-alkyl- P rahvdrn saccharin (Table H) .

Table H Example Alkyl Yield A H 40 B Me 55 C Et 40 D iPr 53 A solution of 2-phenylthiomethyl~4-alkyl-tetrahydro saccharin (1.0 eq) was treated with sulfuryl chloride (1.5 eq) and stirred for 2 hr. The resulting yellow solution was taken to dryness to give 2-chloromethyl-4-alkyl-tetrahydro saccharin, which was treated with 2,6-dichlorobenzoic acid (1.1 eq) , anhydrous potassium carbonate (1.5 eq) and tetrabutylammonium bromide (0.2 - 110 - eq) in DMF (25 mL) at 70°C for 1 hr. The resulting mixture was concentrated in vacuo, diluted with ethyl acetate (100 mL) and filtered. The filtrate was washed with water, saturated NaHC03, water and brine. The organic phase was concentrated in vacuo, and the residue purified by flash chromatography on silica gel (2 : 1 MDC/hexanes) to give 4-alkvl-4.5.6.7-te rahvdro-2-saccharinylmethyl 2.6-dichlorobenzoate (Table J) .

Table J Example Alkyl Yield mp (°o 9A H 63 93-95 9B Me 54 127-129 9C Et 50 86-89 9D iPr 48 108-110 Ex mp e 9E Following a procedure similar to that described for Example 1AA, 2-chloromethyl-4-isopropyl-4, 5, 6, 7-tetrahydrobenzisothiazol-3-one 1,1-dioxide was treated with 2, 6-dichloro-3- t [2- (N, N-dimethylamino) ethyl ] -N-methylaminosulfonyl ] benzoic acid (Preparation 20F) to give 4-isopropyl- .5.6.7-tetrahydro-2-saccharinvlmethvl 2.6-dichloro-3- Γ f2- (N. -dimethylamino)ethvl1-N-methylaminosulfonvllbenzoate hvdrochoride. mp 121 (dec) .

Example 10 Methyl 2.2-dimethvlcvclohexan-6-one carboxvlate : To a suspension of anhydrous Cul (70.0 g, 0.37 mol) in anhydrous ether (500 mL) at 0°C was added halide-free methyl lithium (520 mL of 1.4 M solution in ether, 0.73 mol) . After being stirred at 0°C for 15 minutes, a solution of 3-methyl-2-cyclohexenone (20.0 g, 0.18 mol) in ether (50 mL) was added and stirring continued for another 1 hr. To the resulting mixture was aded THF (50 mL) and HMPA (25 mL) and after 15 min methyl - Ill - cyanoformate (45.0 g, 0.53 mol) in THF (20 mL) and the reaction warmed to room temperature and stirred for 3 r. The reaction mixture was quenched with 2N HC1 (50 mL) . The layers were separated and the aqueous phase extracted with Et20 (1 x 500 mL) . The combined organic extracts were washed with saturated NH4CI solution (3 x 50 mL) , water (2 x 50 mL) , brine (1 x 50 mL) and dried ( a2S04) . Removal of the solvent In vacuo and purification by Kugelrohr distillation afforded 34.0 g (99%) of methyl 2.2-dimethyl cyclohexane-6-one carboxylate. bp 80-84°C/0.6 mm.

The cyclohexanone was converted to . -dimethvl- .5.6.7-tetrahydro-2-saccharinvlmethvl 2.6-dichlorobenzoate. mp 121-123°C, following the procedure described above for Example 9D.

Example 11 Following the procedure of preparation 18A, 5 g of 2-bromo-N,N-dimethylaniline was converted to 3.5 g of N,N-diethyl-2-dimethylaminobenzamide . The amide was reacted by the method of preparation 18B to provide 65 mg of 4-dimethylaminosaccharin, mp 228-229° from ether-hexane. A mixture of 11.1 g of 2, 6-dichlorobenzoyl chloride, 1.9 g of paraformaldehyde and 0.1 g of fused zinc chloride were heated at 100° for 2 hr and then vacuum distilled to yield 3.5 g of chloromethyl 2,6-dichlorobenzoate collected above 145° at aspirator pressure which solidified on cooling, mp 70-72°. To a solution of 4-dimethylaminosaccharin and 0.1 mL of diisopropylethylamine in 1 mL of dry acetonitrile was added 100 mg of chloromethyl 2, 6-dichlorobenzoate . The mixture was stirred at room temparature for 48 hrs and then at 50° for 24 hours, when tic (MDC) showed complete reaction. The mixture was poured into EtOAc and extracted with saturated aHC03 solution. The organic layer was dried and the solvent removed at reduced - 112 - pressure. Chromatography in MDC yielded 15 mg of _i dimethvlamino-2-saccharinylinethvl 2.6-(iichlorobenzoate .

BIOLOGICAL TEST RESULTS Measurement of the inhibition constant, K^, of a HLE-inhibitor complex has been described for "truly reversible inhibition constants" usually concerning competitive inhibitors. [Cha, Biochem. Pharmacol., 2Ar 2177-2185 (1975)]. The compounds of the present invention, however, do not form truly reversible 10 inhibitor complexes but are consumed by the enzyme to some extent. Thus, instead of measuring a K^, a K^* is calculated which is defined as the ratio of the k0ff/kon, the rate of reactivation of the enzyme to the rate of inactivation of the enzyme. The values of k0ff Ϊ5 and kon are measured and Kj_* is then calculated.

The rate of inactivation, kon, of enzymatic activity was determined for the compounds tested by measuring the enzyme activity of an aliquot of the respective enzyme as a function of time after addition 20 of the test compound. By plotting the log of the enzyme activity against time, an observed rate of inactivation, kobs' s obtained which can be represented as kobs = ln2/ti 2 where t^ 2 is the time required for the enzyme activity to drop by 50%. The rate of 5 inactivation is then equal to kon = frpbs [I] where [I] is the concentration of the inhibiting compound .

The reactivation constant, kQff, is similarly 2Q determined, and the inhibition constant, K^*, is then calculated as *i* β *off/kon The values obtained for kon and K^* for specific substituted saccharin derivatives are shown in - 113 - TABLE 4, the compounds being identified by the Example numbers above where their preparations are described. - 114 - TABLE 4 kon X lCT3 Example M"1 sec K* (nM) 1A 375 0.08 IB 522 0.023 1C 28.9 0.40 ID 6.3 8 IE 3.1 18 IF 14 3 1G 3.7 18 1H 9.3 8.5 11 46.0 0.48 1J 670 0.03 IK 250 0.09 1L 77 0.30 1M 92 0.25 IN 3.4 31 1-0 38 2 IP 700 0.17 1Q 900 0.03 1R 460 1.0 IS 30 2.0 IT 15.3 4.0 1U 2000 0.01 IV 3000 0.007 1W 2000 0.01 IX 46 0.5 1Y 192 0.12 1Z 380 0.06 - 115 - kon X 10-3 Example M"1 sec"1 1AA 2300 1AB 1438 1AC 920 IAD 2875 1AE 2556 1AF 2300 1AG 2300 1AH 940 1AI 24.5 1AJ 10 1AK 16 1AM 45 IAN 1.5 1AO 23 1AP 1100 1AQ 923 1AR 857 IAS 769 1AT 714 1AU 333 1AV 435 1AX 1AY 22.3 1AZ 21.5 1BA IBB 100 1BC 1000 1BD 1BE 156 1BF 5.4 1BG 354 1BH 15 1BI 307 - 116 - kon X 10-3 Example M~l sec-1 1BJ 474 1BK 129 1BL 233 IBM 125 1BN 400 1B0 200 IBP 28.6 1BQ 147 1BR 175 IBS 277 1BT 1BU 1BW 51.3 1BX 6.2 1BY 920 1BZ 33 2A 575 2B 1150 2C 2D 1500 3 2300 3B 1091 5A 200.00 5B 281 5C 583 5D 333 5E 880.5 5F 5G 5J 5K 12.3 5L 0.70 - 117 - kon X 10-3 Example -1 sec"1 K*i (nM) 6 583 0.016 7A 320 0.080 7B 331 0.056 8 — 0.600 9A 3.3 18.000 9B 36 1.000 9C 83 0.700 9D 10 1.000 9E 13.3 2.000 10 18.5 1.000 11 35 0.200

Claims (21)

1. 99913/2 - 113 - Claims: 1· Λ compound having the formula: wherein : Ar is phenyl, naphthyi or anthryl or such groups substituted by from one to three, the same or different, members of the group consisting of lower-alkyl, • perfluoro lower-alkyl, perchlorolower-alkyl, lower-alkoxy, 31.X.91 halogen, nitro, cyano, carboxy, 0 ?0 ( lower-alkoxy ) 2 , amino, io er-aikylamino, dilower-alkylamino, lo er-alkancy lamino, lower-a Ikoxycarbon 1, hydroxy, benzyloxy, carboxy iower- alkoxy, -302-N=3, -CO-N=B, - (alkylene) -N=3, -COO (alkylene) - N=B, -UK (alkylene) -N=B; -N (lower-alkyl) - (alkylene) -N=3 or -0- (alkylene) -N=B, where N=3 in each instance is amino, lower-alkylamino, dilower-alkyiamino, 1-azetidinyi, 1- pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinyl, 4-lower-alkyl-l- piperazinyl, 4-benzyl- 1-piperazinyl, 1-imidazolyl, carboxy-lower- 31. x .91 alkylamino or -NR-ialkylenel-NCalkyl^. wherein R is lower alkyl: ' Ft4 is hydrogen, halogen, lower-alkyl, perfiuorolower-alkyi, perchlorolower-alkyl, lower-alkenyl, lower-aikynyi, cyano, amino, lower-alkylamino, dilower- alkylamino, lower-alkoxy, benzyloxy, lower-alkoxycarbon 1 31.X.91 Phenyl or 'car oxamido; and · R5 is hydrogen or from one to two the same o different substituents in any o the 5-, 6- or 7-posicions selected from haloqen, cyano, nitro, =3, i-iower-aikyi-2- 31. X.91 pyrrolvl, lower-alkylsuifonyiamido, polvfluorolower-alkyl-sulfonvlamido, polychlorolower-alkylsulfonylamido, aminosulfonyl, lower-alkyl, polyfluorolower-alkyl, polychlorolower-alkyl, cycloalkyl, lower-alkoxy, hydroxy, 99913/2 - 119 - carboxy, carboxamido, hydroxylower-alkyl, methy lenedioxy , cycloalkyloxy, formyl, aminomethyl, lower-alkylsulfonyl, polyfluorolower-alkylsulfonyl, polychlorolower- naphthyl substituted by from one to two substituents selected from lower-alkyl, lower-alkoxy or halogen and -N=B has the meanings given above; — or R5 is a 5- or 6-membered saturated ring fused to the saccharin at the 5,6 or 6,7 positions, said ring . . u . Λ . . containing two heteroatoms chosen from tne group consisting of nitrogen, oxygen and sulfur or a methylated derivative of said ring; or acid-addition salts of basic compounds of formula I or base-addition salts of acidic compounds of formula I, with the proviso that, when R4 and R^ are both hydrogen, Ar cannot be , either phenyl, 2, -dichlorophenyl or 4-nitrophenyl .

2. A compound according to Claim 1 wherein when R5 is hydrogen, R4 is other than hydrogen or methyl.

3. A compound according to Claim 2 wherein: -Ar is phenyl, naphthyl or anthryl or such groups substituted by from one to three, the same or different, members of the group consisting of lower-alkyl, perfluorolower-alkyl, lower-alkoxy, halogen, nitro, -0 PO (lower-alkoxy) 2, lower-alkanoylamino, hydroxy, carboxy- lower-alkoxy, benzyloxy, -S02~N=3 or -0- (alkylene) -N=B, where N=B is dilower-alkyiamino, l-pyrrolidinyl, 1- piperidinyl, 4-morpho inyl, 1-piperazinyl, 4-lower-alkyl-l- piperazinyl, 4-benzyl-l-piperazinyl, carbox lower-alkylamino or -NR- (alkylene) - (aikyl) 2 where R is lower-alkyl; ^ is hydrogen, primary or secondary lower-alkyl, lower-alkoxy or phenyl; and - 120 R¾ is hydrogen, hydroxy, lower-alkoxy, methylenedioxy, cycloalkyloxy, hydroxylower-alkoxy, polyhydroxylower-alkoxy or acetal or ketal thereof, poly (lower-alkoxy) lower-alkoxy, -O- (alkylene) -C00R, or -0- (alkylene) -N=B, or R5 is a [6,5-g]fused methyl-1, 3-oxazine .

4. A compound according to Claim 3 wherein: Ar is phenyl or phenyl substituted by from one to three, the same or different, members selected from the group consisting of lower-alkyl, lower-alkoxy, halogen, hydroxy, carboxy-lower-alkoxy, benzyloxy, -S02~N=B or -0- (alkylene) -N=B', where N=B is di-lower-alkylamino, 4-morpholinyl, 1-piperazinyl, 4-lower-alkyl-l-piperazinyl, 1-pyrrolidinyl, 1-piperidinyl, 4-benzyl-l-piperazinyl, carboxy-lower-alkylamino or -NR- (alkylene) -N (alkyl) 2, where R is lower-alkyl; R4 is primary or secondary lower-alkyl or lower-alkoxy; and R5 is hydrogen, lower-alkoxy, methylenedioxy, cycloalkyloxy, hydroxylower-alkoxy, polyhydroxylower-alkoxy, or acetal or ketal thereof, pol (lower-alkoxy) lower-alkoxy, -0- (alkylene) -C00R, or 0- (alkylene) -N=B .

5. A compound according to Claim 3 wherein: Ar is phenyl, naphthyl or anthryl, or phenyl substituted by from one to three, the same or different, members selected from the group consisting of lower-alkyl, perfluoro-lower-alkyl, lower-alkoxy, halogen or lower-a1kanoylamino ; R4 is hydrogen, primary or secondary-lower-alkyl, lower-alkoxy or phenyl; and R5 is hydrogen or lower-alkoxy.

6. A compound according to Claim 4 wherein R4 is secondary-lower-alkyl. .

7. A compound according to Claim 5 wherein R4 is orimary or secondary-lower-alkyl. - 121 -

8. A compound according to Claim 5 wherein R4 is lower-alkoxy .

9. A compound according to Claim 3 wherein R4 is primary or secondary lower-alkyl and R5 is hydroxy.

10. A compound according to Claim 9 wherein Ar is phenyl or phenyl substituted by from one to three, the same or different/ members selected from the group consisting of lower-alkoxy, halogen and lower-alkyl.

11. 4-Isopropyl-6-methoxy-2-saccharinylmethyl 2,6- dimethylbenzoate according to Claim 6.

12. 4-Isopropyl-6-methoxy-2-saccharinylmethyl 2,6- dimethoxyben2oate according to Claim 6.

13. 4-Isopropyl-6-methoxy-2-saccharinylmethyl 2,6- dichloro-3- (2- (4-morpholinyl) ethoxylbenzoate according to Claim 6.

14. 4-lsopropyl-6-methoxy-2-saccharinylmethyl 2,6-di- chlorobenzoate according to Claim 6,

15. A compound according to claim 6 selected from the group consisting of 4-Isopropyl-6-methOxy-2*-saccharinylmethyl 2, 6- dichloro-3- (l-piperidinylethoxy) enzoate; 4-Isopropyl-6-methoxy-2-saccharinylmethyl 2,6- dichloro-3-(l-pyrrolidinylethoxy) benzoate; 4-Isopropyl-6-methoxy-2-saccharinylmethyl 2,6- dichloro-3- (2- (N,N-diethylamino) ethoxy] benzoate and 4-lsopropyl-6-methoxy-2-sacchatinylmethyl 2, 6- dichloro-3 [2-

16. A compound according to claim 6 selected from the group consisting of 4-Isopropyl-6-methoxy-2-saccharinylmethyl 2, - dichloro-3- (4-methyl-l-piperazinylsulfonyl) benzoate; and 4~Isopropyl-6-methoxy-2-saccharinylmethyl 2,6- dichloro-3-[-N-[2- (dimethylamino) ethyl 1 -N-methylamino- sulfonyl] benzoate.

17. 4-Isopropyl-6-methoxy-2-saccharinylmethyl 2,6- dichloro-3-hydroxybenzoate according to Claim 6. 'd TiS t¾fr T80 ld3d iNBlbd Qll >)bQ01 T0:ST I66T-100-6c 99913/2 - 122 -

18. A compound according to claim 6 selected from the group consisting of 4-Isopropyl-6-isopropoxy-2-saccharinylmethyl 2, 6-dichlorobenzoate; 4-Isopropyl-6- [2- (2-methoxyethoxy) ethoxy] -2— saccharinylmethyl 2, 6-dichlorobenzoate; 4-Isopropyl-6- [2- (4-morpholinyl) ethoxy] -2-saccharinylmethyl 2, 6-dichlorobenzoate; 4-Isopropyl-6, 7-methylenedioxy-2-saccharinylmethyl 2, 6-dichloro-3- [2-morpholinyl) ethoxy] benzoate; 4-Propyl-5, 6-dimethoxy-2-saccharinylmethyl 2, 6-dichloro-3- [2- (4-morpholinyl) ethoxy] benzoate,· 6-Ethoxy 4-isopropyl-2-saccharinylmethyl 2,6-dichlorobenzoate; 5, 6-Dimethoxy-4-isopropyl-2-saccharinylmethyl 1-naphthyl-carboxylate; > ~ 4-Isopropyl-6, 7-methylenedioxy-2-saccharinylmethyl 2, 6-dichlorobenzoate; 6- (2 , 3-Dihydroxypropoxy) -4-isopropyl-2-saccharinylmethyl 2 , 6-dichlorolower-alkoxycarbonylbenzoate; and 6- ( 2 , 3-Dimethoxypropoxy) -4-isopropyl-2-saccharinylmethyl 2, 6-dichloro-benzoate .

19. A compound according to claim 9 selected from the group consisting of 6- (Benzyloxycarbonyl methoxy-4-isopropyl-2-saccharinylmethyl 2, 6-dichlorobenzoate; 6- (t-Butoxycarbonyl) methoxy-4-isopropyl-2-saccharinylmethyl 2 , 6-dichlorobenzoate; and 4-Isopropyl-6- (methoxycarbonyl) methoxy-2- saccharinylmethyl 2, 6-dichlorobenzoate .

20. 6-Hydroxy-4-isopropylsaccharinylmethyl 2 , 6-dichlorobenzoate according to Claim 9. 99913/2 123 -

21. . A composition for the treatment Of degenerative diseases which comprises a pharmaceutical carrier and an effective proteolytic enzyme inhibiting amount of a compound having the formula: wherein : Ar is phenyl, naphthyl or anthryl or such groups substituted by from one., to three, the same or different, members of the group consisting of lower-alkyl, perfluorolower-alkyl, " perchlorolower-alkyl, lower-alkoxy, 31. X . 91 haiogejn, nitiro, cyano, carbox , 0 PO ( lower-alkony) 2, amino, lower-alkylamino, dilower-alkylamino, lower-alkanoylamino, lower-alkoxycarbonyl, hydroxy, benzyloxy, carbox lower- alkoxy, -S02" =3, -CO-N=B, - (alkylene ) -N=B , -COO (alkylene) - N=B, -NH (alkylene) -N=B; -N ( lower-alkyl) - (alkylene) -N=B, or -0- (alkylene) -N=B, where N=B in each instance is amino, lower-alkylamino, dilower-alkyl-amino, 1-azetidinyl, 1- pyrrolidinyl, l-piperidinyl, -morpholinyl, 1-piperazinyi, 4-lower-alkyl-l-piperazinyl, 4-benzyl-l-piperaziiiyl, 1-imidazolyl, 31 . x . 91 carboxy-lower-alkylamino or -NR-f alkyleneVNfalkyfl , wherein R is lower alkyl; ' is hydrogen, halogen, lower-alkyl, perfLuo olowe -alk l, p chiorolower- lk l, iower-aiken i, iower-aikyny 1 , cyano, amino, lower-alky!amino, dlLcwer— aikyiamino, lower-alkoxy, benzyloxy, lower-alkoxycarbon l 31 . X . 91 phenyl, or 'carboxamido ; and ■ ?*5 is. hydrogen or from one to two th same or differen substituents ir. any of the 5-, β- or T-pcsitions selecte _ 31. X. 9-1 pyrrolyl, polychlorolower-alkylsulfonylamido, aminostilfonyl, lower-alkyl, polyfluorolower-alkyl, polychlorolower-alkyl, cycloalkyl, lower-alkoxy, hydroxy, 99913/2 - 124 - carboxamido, hydroxylower-alk l , meth lenediox cycloalkyloxy, formyl, aminomethyl, lower-alkyisulfonyl, pol fluorolower-alkylsulfon l , polychlorolo er-alkylsulfonyl, lower-alkylsulfony laminosulfonyl, di(lower-alkyl) phosphonoxy, lower-alkoxypoly-lower-alkyleneoxy, hydroxylower-alkoxy, polyhydroxylower-alkoxy, or acetal or ketal thereof, poly ( lower-alkoxy) lower-alkoxy, -3R, -SOR, -SO2R, -OCOR, -0- (alkylene) -C00R, -0- (alkyiene) -MB, where R is lower-alkyl, phenyl, benzyl or naphthyl, or phenyl or naphthyl substituted by from one to two substituents selected from lower-alkyl, lower-alkoxy or halogen and -N=B has the meanings given above; or R5 is a 5- or 6-membered saturated ring fused to the saccharin at the 5,6 or 6,7 positions, said ring containing two heteroatoms chosen from the group consisting of nitrogen, oxygen and sulfur or a methylated derivative of said ring,· or acid-addition salts of basic compounds of formula I or base-addition salts of acidic compounds of formula I, with the proviso that, when R4 and R^ are both hydrogen, Ar cannot be either phenyl, 2, -dichlorophenyl or 4-nitrophenyl . 22,· A composition for the treatment of degenerative diseases which comprises a pharmaceutical carrier and an effective proteolytic enzyme inhibiting amount of a compound according to Claim 4. 23^.· A composition according to Claim 22 wherein R4 is ethyl, isopropyl, n-propyl or sec-butyl. 24 A composition according to Claim 23 wherein R5 is lower-alkoxy, methylenedioxy, polyhydroxylower-alkoxy or acetal or keta>l thereof, poly (lower-alkoxy) lower-alkoxy or -0- (alkylene) -N=B. 99913/2 - 125 - 2<5 A process for preparing a compound according to Claim 1 which comprises reacting a 4-R4-R5-2-halomethyl-saccharin having the formula: with an aryl carboxylic acid having the formula : ArCOOH in the presence of an acid acceptor, where X is halogen and Ar, R4 and R^ have the meanings given in Claim 1. 26. A process for preparing a compound according to Claim 1 which comprises reacting a 2-halomethylsaccharin of formula with a salt of an aryl carboxylic acid having the formula ArCOO * M + wherein X is halogen and Ar, R4 and R5 have the meanings given in Claim 1, and M is an alkali metal or thallium. 99913/2 - 126 - 27. A process according to Claim 25 or 26, wherein the saccharin starting material of formula IV having the formula wherein R c is.' hydrogen,- halogen, lower-alkyl, perfluorolower-alkyl, perchlorolower-alkyl, lower-alkenyl, dilower-alkylamino, lower-alk loxy, or phenyl; R5b is hydrogen, or one or two substituents in any of the 5-, 6-, or 7- positions chosen independently from the group consisting of halogen, cyano, nitro, -N=B ' , 1-lower- alkyl-2-pyrrolyl, lower-alkyl, polyfluorolower-alkyl , polychlorolower-alkyl, cycloalkyl, lower-alkoxy, .X.91 methylenedioxy, cycloalkyloxy, lower-alkylsulfonyl, lower- alkoxypolylower-alkyleneoxy, acetal or ketal of ".X.91 polyhydroxylower-alkoxy, poly (lower-alkoxy) lower-alkoxy, lower-alkylthio, lower-alkylsulfinyl, lower-alkoxycarbonyl, .X.91 -0- (alkylene) -COO (lower-alkyl) , and -O- (alkylene) -N=B ' , and -N=B 1 is dilower-alkylamino, l-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl , 4-lower-alkyl-l-piperazinyl, or 4-benzyl-l- piperazinyl; is prepared by ί reacting a saccharin of formula: with a chlorosilane and formaldehyde, or a formaldehyde equivalent, in the presence of a Lewis acid. 99913/2 - 127 - 28. A process according to Claim 27 further characterized in that said process is carried out in 1,2- dichloroethane, said formaldehyde equivalent is paraformaldehyde, said chlorosilane is chlorotrimethyl- silane and said Lewis acid is stannic chloride. 29. A process according to Claim 27 or 28 wherein a starting material of the formula • wherein R b is hydrogen, secondary or tertiary lower-alkyl, perfluorolo.wer-alkyl , perchiorolower- alkyl, lower-alkox , fluorine, chlorine, dilower-aikylamino, or benzyloxy, R5a is hydrogen, or one or two substituents independently chosen from the group consisting of chlorine, fluorine, N=8 ' , perfluorolower-alkyl , secondary or tertiary 1.X.SI lower-alkyl, cycloalkyl, lower-alkoxy, methylenedioxy , lower-alkoxypol lower-alkyleneoxy, pol (lower-alkoxy) lower Γ.Χ.91 alkoxy, acetal or ketal of polyhydroxylower-alkoxy , and -0- (aikylene) -N=B ' and N=B ' is dilower-aikylamino, 1- pyrrolidinyl, l-piperidinyl , 4-morpholinyl , 4-lower-alkyl-l- piperazinyl, or '4-benzyl-l-piperazinyl . is prepared by reacting a 2-R4b-R5a- , N-di-lower-aikylben: amide having the formula: (Alkyl) 2 R 99913/2 - 128 - where Alkyl is lower-alkyl, with one molar equivalent of a lower-alkyl alkali metal; reacting the resulting alkali metal salt either with sulfur dioxide followed by hydroxylamine-O-sulfonic acid in the presence of base or with a sulfuryl halide followed by ammonia; heating the resulting 2-R4b-R5a-6-aminosulfonyl-N, N-di- lower-alkylbenzamide having the formula: in a lower-alkanoic acid; and treating the resulting 4-R4D- R^a-saccharin di-lower-alkylammonium salt with aqueous acid 30. A process for preparing a compound according to Claim 1 which comprises reacting a saccharin of formula with a chloromethyl ester of an aryl carboxylic acid of formula ArCOOCH2Cl in the presence of an acid acceptor, where Ar,- R4 and R5 have the meanings given, in Claim 1. 99913/2 - 129 - 31. A process according to any of Claims 27, 28 and 30 wherein a starting material of the formula wherein R8 is lower-alkyl, is prepared by "acting a compound of formula where Alkyl is lower-alkyl with an alkali metal dialkylamide such as lithium diathylamide, . followed by a chlorosilane to form a benzylic silyl compound which is treated with one molar equivalent, of a lower-alkyl . alkali metal; reacting the resulting alkali metal salt either with sulfur dioxide' followed by hydroxyIamine-O-sulfonic acid in the presence of base or with a sulfuryl halide followed by ammonia; heating the resulting 6-aminosulfonyl-N, N-dilower-alkylbenzamide having the formula: in a lower-aikanoic acid; and treating the resulting saccharin with a source of fluoride anion. - 130 - A compound according to claim 1 having the formula: wherein: ΛΓ is phenyl, naphthyl or anthryl or such groups substituted by Crom one to three, the same or different, members of the group consisting of lower-alkyl, perfluoro-lower-alkyl, perchloro-lower-alky 1, lower-alkoxy, halogen, cyano, carboxy, amino, lo er-alkylamino, d i-lower-alkylamino, lower-alkanoylamino, lower-alkoxycarboxyl / , hydroxy, benzyloxy, carboxy-lower-alkoxy , -SO.,-N=B, -CO-N=B, - ( alky lene) -M=D , -COO(alkylene) -N=B, -NH(alkylene) -N=B, -N(lower-alyl) -(alkylene)--N=B, or -O-(alkylene) -N=B, where N=B in each instance is amino, lower-alkylamino, di-lower-alkylamino, 1-azetidinyl, 1-pyr rolid iny , 1-piperid inyl, 4-morpholinyl, 1-piperazinyl, 4-lower-alkyl-l-piperazinyl, 4-benzyi-l-piperazinyl, 1-imidazolyl or ca rboxy-lower-alkylamino; is hydrogen, halogen, ■ p imary or secondary lower-alkyl, per f luoro-lower-alkyl, 'perchloro-lower-alkyl, lower-alkenyl, lower-alkynyl, cyano, amino, lower-alkylamino, di- lower-alkylamino, lower-alkoxy, lower-alkoxycarboxyl or phenyl; and - Π,. is hydrogen or from one to two subs ituents in any of the 5-, 6- or 7-positions selected from halogen, cyano, nitro, N=D, lower-alkylsulfonylamido, , polvC luoro-lower-alkyl- 99913/2 - 131 - . I.X.91 sulfonylamido, polychloro-lower-alkylsulfonylamido, ~ amino- sulfonyl, lower-alkyl, polyf luoro-lowe r-alkyl, polychloro- lower-alkyl, cycloalkyl, lower-alkoxy , hydroxy, carboxy, carboxamido, hydroxy-lower-alkyl,. formyl, aminomethyl, lower- alkylsulfonyl, polyf luoro-lower-alkylsulfonyl , polychloro- lower-alkylsulfonyl, lowe r-alk lsulfonylam inosul Cony1, lo ec- alkoxypoly-lower-alkyleneoxy , -SR, -SOR, -S°2R o -OCOR, where R is lower-alkyl, phenyl or naphthyl, or phenyl or naphthyl substituted by from one to two substituents selected from lower-alkyl, lower-alkoxy or halogen and -N=B has the meanings given above; or acid-addition salts of basic compounds of formula .X.91 la or base addition salts of acidic compounds of formula la; with the proviso that, when R^ and 5 are both hydrogen, At cannot be either phenyl, 2 , 4 -d chlorophenyl or -ni trophenyl. 33, Λ composition for the treatment of degenerative diseases which comprises a pharmaceutical carrier and an effective proteolytic enzyme inhibiting amount of a compound having the formula: wherein: Ar is phenyl, naphthyl or anthryl or such groups substituted by from one to three, the same or different, members of the group consisting off lower-alkyl, perfluoro- lower-alkyl, perchloro-lower-alkyl, lower-alkoxy, halogen, cyano, carboxy, amino, lower-alkylamino, d -lower-alkylamino, lowe r -a lk anoylamino , lower-alkoxycarboxyl , hyd roxy , benz y lox y , carboxy-lower-alkoxy, -S02~N=D, -CO-N=D, - (alkylene) - =Π , -COO(alkylene) -N=B or -0- ( alkylene) -N=B, where M=B in each instance is amino, lower-alkylamino, di-.lower-a.lkyl- 99913/2 - 132 - amido , -Nil (alkylene) -N=D ; -N ( lowe r -alky1) -(alkylene) -N=D , 1-azetidinyl, 1-pyr olid inyl, 1-p iper id in 1, 4-morpholiny 1 , 1-piperazinyl, 4-lower-alkyl-l-piperaz inyl, -benz 1- -piperazinyl, l-imidazolyl or cacboxy-lower-alkylamino; ^ is hydrogen, halogen, primary or secondary lower-a lk y l , pecCluoro-lower-alkyl, perchloro-lower- a lk y 1, lower-alkenyl, lower-alkyn 1 , cyano, amino, lower-alkylamino, di-lower-alkylamino, lower-alkoxy, lower-alkoxycarboxyl or phenyl; and ^ is hydrogen or Crom one to two substituents in any oC the 5-, 6- or 7-positions selected from halogen, cyano, nitro, N=D, lower-alkylsulEony lamino, polyf lucro-lowe r-alkyl-sulfonylamido, , polychloro-lower-alkylsulConylamino, amino-sulfonyl, lower-alk y l , po ly f luoro-lower-alkyl, polychloro-lower-alkyl, cycloalkyl, lower-alkoxy, hydroxy, carboxy, carboxamido, hydroxy-lower-alkyl, , formyl, aminomethyl, lower-alkylsul£onyl, polyliluoro-lower-alkylsulConyl, poly-ch loro-lower -alky Isul Cony1, lower-aIky Isulfon laminosul Cony 1 , lowe -alkoxypoly-lower-alkyleneoxy , -SR , -SOR , ~S0R2 or -OCOR , where R is lower-alkyl, phenyl or naphthyl, or phenyl or naphthyl substituted by £ro.m one to two substituents selected from lower-alkyl, lower-alkoxy or halogen and -M=D has the meanings given above, or a pharmaceutically acceptable acid-addition salt of a basic compund of formula la or a pharmceutically acceptable base-addition salt of an acidic compound of formula la. 99913/2 133 - 34. A process Cor preparing a compound according Lo Claim 32 which comprises reacting a 4 -Ν,.-2-haloriie thy .1. -saccharin having the formula: with an, aryl cacboxyiic acid having the Cormula: ArCOOII in the presence oC an acid acceptor, whfere X is halogen and At, Ri and R- have the meanings given in Claim 32(. For the Applicants, DR. REINHGiLD COHN AND PARTNERS